The present invention relates to novel sulfonamide derivatives having excellent matrix metalloproteinase 13 inhibitory action and aglycanase inhibitory action, and to pharmaceutical compositions containing the same.
A nonsteroidal anti-inflammatory drug (NSAID) is conventionally used for the treatment of osteoarthritis and chronic rheumatoid arthritis. However, such therapeutic methods are only symptomatic therapies, and there are still no medicaments for etiotropic therapy that inhibits the progress of these diseases.
In addition, in the field of antitumor drugs, since drugs currently used in the clinical setting are generally associated with strong adverse side effects, there is a need for drugs that are effective for not only the treatment of cancer, but also for both the prevention of the disease and the prevention of relapse and that cause only mild adverse side effects, if any.
Matrix metalloproteinase (hereinafter referred to as xe2x80x9cMMPxe2x80x9d) is known to be an enzyme that decomposes protein components of connective tissue. MMP-13 (collagenase-3), which is one of several subtypes of MMP, has strong decomposition activity against type II collagen, one of the main components of joint cartilage. MMP-13 is an enzyme that is found locally in joints, and its expression has been reported to be elevated in the joints of patients with osteoarthritis and chronic rheumatoid arthritis as compared with that in the joints of healthy people (P. G. Mitchell et al., Journal of Clinical Investigation, vol. 97, 761-768, 1996; P. Reboul et al., Journal of Clinical Investigation, vol. 97, 2011-2019, 1996; D. Wemicke et al., Journal of Rheumatology, vol. 23, 590-595, 1996). Based on these reports, MMP-13 is considered to play an important role in the destruction of joint cartilage matrix in the course of development of arthritis.
In addition, aglycan, another main component of joint cartilage, is reported to be decomposed by an enzyme referred to as aglycanase in osteoarthritis. Although the actual form of aglycanase has not been identified, this enzyme is known to cleave aglycan at an extremely characteristic sequence of Glu373-Ala374 (J. D. Sandy et al., Journal of Biological Chemistry, vol. 266, 8683-8685, 1990; J. D. Sandy et al., Journal of Biological Chemistry, vol. 270, 2550-2556, 1995).
Thus, on the basis of the above findings, compounds that strongly inhibit both MMP, particularly MMP-13, and aglycanase are considered to be useful as therapeutic and preventive agents against osteoarthritis and other forms of arthritis.
On the other hand, MMP-13 is known to be expressed at a high level in breast carcinoma and several other cancerous tissues, and it has been indicated that it has a strong possibility of playing an important role in the growth and metastasis of these cancers (J. M. P. Freije et al., Journal of Biological Chemistry, vol. 269, 16766-16773, 1994). Thus, compounds that have inhibitory action against this enzyme are considered to be useful inhibitors of metastasis, invasion and growth of various cancer cells.
Compounds having MMP inhibitory activity, for example, those shown below, are disclosed in WO 97/27174. However, the inhibitory action of these compounds against MMP-13 is not disclosed, and there is no disclosure or suggestion of aglycanase inhibitory action. 
As a result of earnest research on the synthesis and pharmacological action of compounds that strongly inhibit both MMP-13 and aglycanase, the inventors of the present invention found that novel sulfonamide derivatives have potent MMP-13 inhibitory activity and aglycanase inhibitory activity, thereby leading to completion of the present invention.
The present invention relates to
(1) a compound of the following formula (I) or a pharmacologically acceptable salt, ester or other derivative thereof: 
{wherein
R1 represents a hydroxyl group or a hydroxyamino group;
R2 represents a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with at least one group selected from Substituent group xcex1, a cycloalkyl group having from 3 to 7 carbon atoms or a group of the formula: xe2x80x94Axe2x80x94R6 
[wherein
A represents a lower alkylene group or a lower alkylene group interrupted by an oxygen atom, xe2x80x94S(O)mxe2x80x94 or xe2x80x94N(R9)xe2x80x94;
R6 represents a group of the following formula (II), (III) or (IV): 
(wherein
X represents an oxygen atom, a sulfur atom, xe2x80x94N(R10)xe2x80x94 or xe2x80x94C(R11)(R12);
Y represents an oxygen atom, a carbonyl group, xe2x80x94S(O)nxe2x80x94, xe2x80x94N(R10)xe2x80x94 or xe2x80x94C(R11)(R12);
R7 and R8 may be the same or different from each other and each represents a hydrogen atom, a lower alkyl group, a carboxyl group, one group selected from Substituent group xcex1, a lower alkyl group substituted with at least one group selected from Substituent group xcex1, a lower alkoxy group substituted with at least one group selected from Substituent group xcex1, a lower alkylthio group substituted with at least one group selected from Substituent group xcex1, a lower alkylsulfinyl group substituted with at least one group selected from Substituent group xcex1 or a lower alkylsulfonyl group substituted with at least one group selected from Substituent group xcex1, or R7 and
R8 may form, together with the carbon atom(s) to which they are attached, a non-aromatic hydrocarbon ring, a non-aromatic heterocycle, a non-aromatic hydrocarbon ring substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2, a non-aromatic heterocycle substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2, an aryl ring, a heteroaryl ring, an aryl ring substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2 or a heteroaryl ring substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2; and
R9, R10, R11 and R12 may be the same or different from one another and each represents a hydrogen atom or a lower alkyl group, and further R11 and R12 may form, together with the carbon atom(s) to which they are attached, a non-aromatic hydrocarbon ring, a non-aromatic heterocycle, a non-aromatic hydrocarbon ring substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2 or a non-aromatic heterocycle substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2,
with the proviso that when R7 and R8 are attached to the same carbon atom, R7 and R8 do not form, together with the carbon atom to which they are attached, an aryl ring, a heteroaryl ring, an aryl ring substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2 or a heteroaryl ring substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2), and
m and n may be the same or different from each other and each represents 0, 1 or 2],
R3 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group having from 3 to 7 carbon atoms, an alkenyl group, an alkynyl group, a lower alkyl group substituted with at least one group selected from Substituent group xcex1, a cycloalkyl group having from 3 to 7 carbon atoms substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2, an alkenyl group substituted with at least one group selected from Substituent group xcex1 or an alkynyl group substituted with at least one group selected from Substituent group xcex1;
R4 represents an arylene group, a heteroarylene group, an arylene group substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2 or a heteroarylene group substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2; and
R5 represents a lower alkyl group, a lower alkyl group substituted with at least one group selected from Substituent group xcex1, an aryl group, a heteroaryl group, an aryl group substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2 or a heteroaryl group substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2;
with the proviso that when R2 represents a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with at least one group selected from Substituent group xcex1 or a cycloalkyl group having from 3 to 7 carbon atoms, R3 represents alkynyl or an alkynyl group substituted with at least one group selected from Substituent group xcex1.
[Substituent Group xcex1]
halogen atoms, cycloalkyl groups having from 3 to 7 carbon atoms, lower alkoxy groups, halogeno lower alkoxy groups, lower alkanoyl groups, lower alkylthio groups, halogeno lower alkylthio groups, lower alkylsulfinyl groups, lower alkylsulfonyl groups, amino groups, mono-lower alkylamino groups, di-(lower alkyl)amino groups, cyano groups, nitro groups, aryl groups, heteroaryl groups, aryloxy groups, heteroaryloxy groups, arylthio groups, heteroarylthio groups, aryl groups substituted with at least one group selected from Substituent group xcex3, heteroaryl groups substituted with at least one group selected from Substituent group xcex3, aryloxy groups substituted with at least one group selected from Substituent group xcex3, heteroaryloxy groups substituted with at least one group selected from Substituent group xcex3, arylthio groups substituted with at least one group selected from Substituent group xcex3, heteroarylthio groups substituted with at least one group selected from Substituent group xcex3,
[Substituent Group xcex2]
lower alkyl groups, halogeno lower alkyl groups,
[Substituent Group xcex3]
halogen atoms, lower alkyl groups, halogeno lower alkyl groups, lower alkoxy groups, halogeno lower alkoxy groups, lower alkylthio groups, halogeno lower alkylthio groups, nitro groups, cyano groups.
Of these compounds, preferred are:
(2) a compound in which R1 is a hydroxyamino group;
(3) a compound in which R2 is an alkyl group having from 1 to 4 carbon atoms or an alkyl group having from 1 to 4 carbon atoms substituted with at least one group selected from Substituent group xcex1;
(4) a compound in which R2 is an alkyl group having from 1 to 4 carbon atoms or an alkyl group having from 1 to 4 carbon atoms substituted with at least one group selected from the following Substituent group xcex11;
(5) a compound in which R2 is an alkyl group having from 1 to 4 carbon atoms or an alkyl group having from 1 to 4 carbon atoms substituted with at least one group selected from the following Substituent group xcex12;
(6) a compound in which R2 is a methyl, ethyl, propyl, isopropyl, 2-methoxyethyl, 2-methylthiophenyl, 3,3,3-trifluoropropyl, benzyl, 2-phenylethyl, benzyloxymethyl, benzylthiomethyl or 2-thienylthiomethyl group;
(7) a compound in which A is an alkylene group having from 1 to 4 carbon atoms or a lower alkylene group interrupted by an oxygen atom or xe2x80x94S(O)mxe2x80x94;
(8) a compound in which A is a methylene, ethylene, 1,1-dimethylethylene, trimethylene, tetramethylene, xe2x80x94CH2O(CH2)2xe2x80x94 or xe2x80x94CH2S(CH2)2xe2x80x94 group;
(9) a compound in which A is a methylene, ethylene or trimethylene group;
(10) a compound in which R6 is 
(11) a compound in which R3 is a hydrogen atom, a lower alkyl group, a cycloalkyl group having from 3 to 7 carbon atoms, an alkenyl group, an alkynyl group, a lower alkyl group substituted with an aryl group, a lower alkyl group substituted with a heteroaryl group, an alkenyl group substituted with an aryl group, an alkenyl group substituted with a heteroaryl group, an alkynyl group substituted with an aryl group or an alkynyl group substituted with a heteroaryl group (here, the xe2x80x9caryl groupxe2x80x9d and the xe2x80x9cheteroaryl groupxe2x80x9d are unsubstituted or substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2, described above);
(12) a compound in which R3 is an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 7 carbon atoms, an alkenyl group having from 3 to 6 carbon atoms, an alkynyl group having from 3 to 6 carbon atoms, an alkyl group having from 1 to 3 carbon atoms substituted with an aryl group, an alkyl group having from 1 to 3 carbon atoms substituted with a heteroaryl group, an alkenyl group having 3 carbon atoms substituted with an aryl group, an alkenyl group having 3 carbon atoms substituted with a heteroaryl group, an alkynyl group having 3 carbon atoms substituted with an aryl group or an alkynyl group having 3 carbon atoms substituted with a heteroaryl group;
(13) a compound in which R3 is a methyl, ethyl, propyl, cyclopropyl, allyl, 2-butenyl, propargyl, 2-butynyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 3-(4-chlorophenyl)-propyl, 3-phenylpropargyl or 3-(4-chlorophenyl)propargyl group;
(14) a compound in which R4 is a phenylene, naphthylene or thienylene group;
(15) a compound in which R4 is a p-phenylene group;
(16) a compound in which R5 is an alkyl group having from 1 to 6 carbon atoms, a halogenoalkyl group having from 1 to 4 carbon atoms, an aryl group, a heteroaryl group, an aryl group substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2 or a heteroaryl group substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2;
(17) a compound in which R5 is a methyl, ethyl, propyl, butyl, trifluoromethyl, phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3-pyridyl, 4-pyridyl, 2-thienyl or 3-thienyl group;
(18) a compound in which R7 and R8 may be the same or different from each other and each represents a hydrogen atom, a nitro group, an amino group, a mono-lower alkylamino group, a di(lower alkyl)amino group, a cyano group, a carboxyl group, a halogen atom, an aryl group, a heteroaryl group, a lower alkyl group, a lower alkanoyl group, a lower alkyl group substituted with at least one group selected from Substituent group xcex1, a lower alkoxy group substituted with at least one group selected from Substituent group xcex1, a lower alkylthio group substituted with at least one group selected from Substituent group xcex1, a lower alkylsulfinyl group substituted with at least one group selected from Substituent group xcex1 or a lower alkylsulfonyl group substituted with at least one group selected from Substituent group xcex1, or R7 and R8 form, together with the carbon atom(s) to which they are attached, a non-aromatic hydrocarbon ring, a non-aromatic heterocycle, a non-aromatic hydrocarbon ring substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2, a non-aromatic heterocycle substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2, an aryl ring, a heteroaryl ring, an aryl ring substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2 or a heteroaryl ring substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2;
(19) a compound in which R7 and R8 may be the same or different from each other and each represents a hydrogen atom, a nitro group, a cyano group, a carboxyl group, a halogen atom, an aryl group, a heteroaryl group, a lower alkyl group, a lower alkanoyl group or a lower alkyl group substituted with at least one group selected from Substituent group xcex1, or R7 and R8 form, together with the carbon atom(s) to which they are attached, a non-aromatic hydrocarbon ring, a non-aromatic heterocycle, a non-aromatic hydrocarbon ring substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2, a non-aromatic heterocycle substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2, an aryl ring, a heteroaryl ring, an aryl ring substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2 or a heteroaryl ring substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2;
or a pharmacologically acceptable salt, ester or other derivative thereof.
[Substituent Group xcex11]
halogen atoms, cycloalkyl groups having from 3 to 7 carbon atoms, lower alkoxy groups, lower alkylthio groups, amino groups, mono-lower alkylamino groups, di-(lower alkyl)amino groups, cyano groups, aryl groups, heteroaryl groups, aryloxy groups, heteroaryloxy groups, arylthio groups, heteroarylthio groups.
[Substituent Group xcex12]
lower alkoxy groups, lower alkylthio groups, aryl groups, heteroaryl groups, aryloxy groups, heteroaryloxy groups, arylthio groups, heteroarylthio groups.
In the above compounds, particularly preferred are:
(20) a compound selected from the following compounds or a pharmacologically acceptable salt, ester or other derivative thereof:
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)-2-(2-phthalimidoethyl)glycinamide,
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)-2-[2-(thiazolidin-2,4-dione-3-yl)ethyl]glycinamide,
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)-2-[2-(quinazolin-2,4-dione-3-yl)ethyl]glycinamide,
(xc2x1)-2-[2-(5-fluoropyrimidin-2,4-dione-3-yl)ethyl]-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide,
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)-2-[2-(thieno[3,2-d]pyrimidin-2,4-dione-3-yl)ethyl]glycinamide,
(xc2x1)-N-hydroxy-Nxcex1-methyl-2-[2-(7-methylxanthin-1-yl)ethyl]-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide,
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)-2-[2-pteridin-2,4-dione-3-yl)ethyl]glycinamide,
(xc2x1)-2-[2-(1,1-dioxo-1,2-benzisothiazol-3-one-2-yl)ethyl]-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide,
(xc2x1)-N-hydroxy-Nxcex1-methyl-2-[2-(6-methylpyrimidin-2,4-dione-3-yl)ethyl]-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide,
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)-2-[2-(5-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]glycinamide,
N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)-2(R)-(2-phthalimidoethyl)glycinamide,
(xc2x1)-Nxcex1-[4-(4-fluorophenoxy)benzenesulfonyl]-N-hydroxy-Nxcex1-methyl-2-(2-phthalimidoethyl)glycinamide,
(xc2x1)-2-[2-(6-chloropyrimidin-2,4-dione-3-yl)ethyl]-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide,
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)-2-[2-(6-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]glycinamide,
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-[4-(pyridin-4-yl)oxybenzenesulfonyl]-2-[2-thieno[3,2-d]pyrimidin-2,4-dione-3-yl)ethyl]glycinamide,
(xc2x1)-2-[2-(6-chloro-1-methylpyrimidin-2,4-dione-3-yl)ethyl]-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide,
(xc2x1)-Nxcex1-[4-(4-chlorophenoxy)benzenesulfonyl]-2-[2-(6-chloropyrimidin-2,4-dione-3-yl)ethyl]-N-hydroxy-Nxcex1-methylglycinamide,
(xc2x1)-2-[2-(6-chloropyrimidin-2,4-dione-3-yl)ethyl-Nxcex1-[4-(4-fluorophenoxy)-benzenesulfonyl]-N-hydroxy-Nxcex1-methylglycinamide,
(xc2x1)-Nxcex1-[4-(4-chlorophenoxy)benzenesulfonyl]-N-hydroxy-Nxcex1-methyl-2-[2-(6-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]glycinamide,
(xc2x1)-Nxcex1-[4-(4-fluorophenoxy)benzenesulfonyl]-N-hydroxy-Nxcex1-methyl-2-[2-(6-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]glycinamide,
(xc2x1)-Nxcex1-[4-(3-chlorophenoxy)benzenesulfonyl]-N-hydroxy-Nxcex1-methyl-2-[2-(6-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]glycinamide,
(xc2x1)-Nxcex1-[4-(3-chlorophenoxy)benzenesulfonyl]-2-[2-(6-chloropyrimidin-2,4-dione-3-yl)ethyl]-N-hydroxy-Nxcex1-methylglycinamide,
(xc2x1)-2-[2-(6-chloropyrimidin-2,4-dione-3-yl)ethyl]-Nxcex1-ethyl-N-hydroxy-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide,
(xc2x1)-2-[2-(6-chloropyrimidin-2,4-dione-3-yl)ethyl]-Nxcex1-[4-(3-fluorophenoxy)-benzenesulfonyl]-N-hydroxy-Nxcex1-methylglycinamide,
(xc2x1)-2-[2-(6-chloropyrimidin-2,4-dione-3-yl)ethyl]-N-hydroxy-Nxcex1-methyl-Nxcex1-[4-(pyridin-4-yl)oxybenzenesulfonyl]glycinamide,
(xc2x1)-Nxcex1-[4-(3-fluorophenoxy)benzenesulfonyl]-N-hydroxy-Nxcex1-methyl-2-[2-(6-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]glycinamide,
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-[4-(pyridin-4-yl)oxybenzenesulfonyl]-2-[2-(6-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]glycinamide,
(xc2x1)-Nxcex1-ethyl-N-hydroxy-Nxcex1-(4-phenoxybenzenesulfonyl)-2-[2-(6-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]glycinamide,
(xc2x1)-N-hydroxy-Nxcex1-methyl-2-[2-(1-methyl-6-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide,
(xc2x1)-2-[2-(5-chloropyrimidin-2,4-dione-3-yl)ethyl]-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide,
Nxcex1-[4-(3-chlorophenoxy)benzenesulfonyl]-N-hydroxy-Nxcex1-methyl-2-[2-quinazolin-2,4-dione-3-yl)ethyl]glycinamide,
Nxcex1-[4-(3-chlorophenoxy)benzenesulfonyl]-N-hydroxy-Nxcex1-methyl-2-[2-(thieno[3,2-d]pyrimidin-2,4-dione-3-yl)ethyl]glycinamide, and
Nxcex1-[4-(3-chlorophenoxy)benzenesulfonyl]-N-hydroxy-Nxcex1-methyl-2-(2-phthalimidoethyl)glycinamide.
Another object of the present invention is to provide:
(21) a medicament (particularly a MMP-13 inhibitory agent and an aglycanase inhibitory agent) containing the compound described in any one selected from the above (1) to (20) or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient, more specifically
(22) the medicament described in (21) for the prevention or treatment of arthritis (particularly osteoarthritis), or
(23) the medicament described in (21) for inhibiting metastasis, invasion or growth of cancer (particularly breast cancer).
Furthermore, the present invention also provides
(24) a method for preventing or treating arthritis (particularly osteoarthritis) or a method for inhibiting metastasis, invasion or growth of cancer (particularly breast cancer), comprising administering the compound or a pharmacologically acceptable salt, ester or other derivative thereof described in any one of the above-mentiond (1) to (20), and
(25) a use of the compound or a pharmacologically acceptable salt, ester or other derivative thereof described in any one of the above-mentiond (1) to (20) for manufacturing a medicament for the prevention or treatment of arthritis (particularly osteoarthritis) or a medicament for inhibiting metastasis, invasion or growth of cancer (particularly breast cancer).
In the above formula (I):
the xe2x80x9clower alkyl groupxe2x80x9d in the definition of R2, R3, R5, R7, R8, R9, R10, R11, R12, xe2x80x9cSubstituent group xcex2xe2x80x9d and xe2x80x9cSubstituent group xcex3xe2x80x9d; the xe2x80x9clower alkyl groupxe2x80x9d of the xe2x80x9clower alkyl group substituted with at least one group selected from Substituent group xcex1xe2x80x9d in the definition of R2, R3, R5, R7 and R8; the xe2x80x9clower alkylxe2x80x9d moiety of the xe2x80x9clower alkoxy group substituted with at least one group selected from Substituent group xcex1xe2x80x9d, the xe2x80x9clower alkylthio group substituted with at least one group selected from Substituent group xcex1xe2x80x9d, the xe2x80x9clower alkylsulfinyl group substituted with at least one group selected from Substituent group xcex1xe2x80x9d and the xe2x80x9clower alkylsulfonyl group substituted with at least one group selected from Substituent group xcex1xe2x80x9d in the definition of R7 and R8; the xe2x80x9clower alkylxe2x80x9d moiety of the xe2x80x9clower alkoxy groupxe2x80x9d, the xe2x80x9chalogeno lower alkoxy groupxe2x80x9d, the xe2x80x9clower alkylthio groupxe2x80x9d, the xe2x80x9chalogeno lower alkylthio groupxe2x80x9d, the xe2x80x9clower alkylsulfinyl groupxe2x80x9d, the xe2x80x9clower alkylsulfonyl groupxe2x80x9d, the xe2x80x9cmono-lower alkylamino groupxe2x80x9d and the xe2x80x9cdi-(lower alkyl)amino groupxe2x80x9d in the definition of xe2x80x9cSubstituent group xcex1xe2x80x9d; the xe2x80x9clower alkylxe2x80x9d moiety of the xe2x80x9chalogeno lower alkyl groupxe2x80x9d in the definition of the xe2x80x9cSubstituent group xcex2xe2x80x9d; and the xe2x80x9clower alkylxe2x80x9d moiety of the xe2x80x9chalogeno lower alkyl groupxe2x80x9d, the xe2x80x9clower alkoxy groupxe2x80x9d, the xe2x80x9chalogeno lower alkoxy groupxe2x80x9d, the xe2x80x9clower alkylthio groupxe2x80x9d and the xe2x80x9chalogeno lower alkylthio groupxe2x80x9d in the definition of xe2x80x9cSubstituent group xcex3xe2x80x9d represent a straight or branched chain alkyl group having from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl and 1,2,2-trimethylpropyl groups, preferably a straight or branched chain alkyl group having from 1 to 4 carbon atoms, particularly preferably a methyl, ethyl, propyl, isopropyl or butyl group.
The xe2x80x9ccycloalkyl group having from 3 to 7 carbon atomsxe2x80x9d in the definition of R2, R3 and the xe2x80x9csubstituent group xcex1xe2x80x9d; and the xe2x80x9ccycloalkyl group having from 3 to 7 carbon atomsxe2x80x9d of the xe2x80x9ccycloalkyl group having from 3 to 7 carbon atoms substituted with a group selected from the substituent group xcex1 and the substituent group xcex2xe2x80x9d in the definition of R3 include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.
The xe2x80x9clower alkylene groupxe2x80x9d in the definition of A represents a straight or branched alkylene group having from 1 to 6 carbon atoms such as methylene, ethylene, trimethylene, propylene, tetramethylene, 1,1-dimethylethylene, 1,1-dimethyltrimethylene and 1,1-dimethyltetramethylene, preferably a straight or branched alkylene group having from 1 to 4 carbon atoms, more preferably a straight alkylene group having from 1 to 4 carbon atoms, particularly preferably a methylene, ethylene or trimethylene group.
The xe2x80x9clower alkylene group interrupted by an oxygen atom, xe2x80x94S(O)mxe2x80x94 xe2x80x9cor xe2x80x94N(R9)xe2x80x94xe2x80x9d in the definition of A represents a group in which an oxygen atom, xe2x80x94S(O)mxe2x80x94 or xe2x80x94N(R9)xe2x80x94 is present between two carbon atoms of the above xe2x80x9clower alkylene groupxe2x80x9d, and preferred examples of such a group include xe2x80x94CH2OCH2xe2x80x94, xe2x80x94CH2SCH2xe2x80x94, xe2x80x94CH2NHCH2xe2x80x94, xe2x80x94CH2N(CH3)CH2xe2x80x94, xe2x80x94CH2OCH2CH2xe2x80x94, xe2x80x94CH2SCH2CH2xe2x80x94, xe2x80x94CH2NHCH2CH2xe2x80x94, xe2x80x94CH2N(CH3)CH2CH2xe2x80x94, xe2x80x94CH2SOCH2CH2xe2x80x94 and xe2x80x94CH2SO2CH2xe2x80x94.
The xe2x80x9clower alkoxy groupxe2x80x9d in the definition ofxe2x80x9cSubstituent group xcex1xe2x80x9d and xe2x80x9cSubstituent group xcex3xe2x80x9d; and the xe2x80x9clower alkoxy groupxe2x80x9d of the xe2x80x9clower alkoxy group substituted with at least one group selected from Substituent group xcex1xe2x80x9d in the definition of R7 and R8 represent a group in which an oxygen atom is attached to the above xe2x80x9clower alkylxe2x80x9d group, preferably a straight or branched alkoxy group having from 1 to 4 carbon atoms, more preferably a methoxy, ethoxy, propoxy, isopropoxy or butoxy group, particularly preferably a methoxy, ethoxy or propoxy group.
The xe2x80x9clower alkylthio groupxe2x80x9d in the definition of xe2x80x9cSubstituent group xcex1xe2x80x9d and xe2x80x9cSubstituent group xcex3xe2x80x9d; and the xe2x80x9clower alkylthio groupxe2x80x9d of the xe2x80x9clower alkylthio group substituted with at least one group selected from Substituent group xcex1xe2x80x9d in the definition of R7 and R8 represent a group in which a sulfur atom is attached to the above xe2x80x9clower alkylxe2x80x9d group, preferably a straight or branched alkylthio group having from 1 to 4 carbon atoms, more preferably a methylthio, ethylthio, propylthio, isopropylthio or butylthio group, particularly preferably a methylthio, ethylthio or propylthio group.
The xe2x80x9clower alkylsulfinyl groupxe2x80x9d in the definition of xe2x80x9cSubstituent group xcex1xe2x80x9d; and the xe2x80x9clower alkylsulfinyl groupxe2x80x9d of the xe2x80x9clower alkylsulfinyl group substituted with at least one group selected from Substituent group xcex1xe2x80x9d in the definition of R7 and R8 represent a group in which a sulfinyl moiety (xe2x80x94SOxe2x80x94) is attached to the above xe2x80x9clower alkylxe2x80x9d group, preferably a straight or branched alkylsulfinyl group having from 1 to 4 carbon atoms, more preferably a methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl or butylsulfinyl group, particularly preferably a methylsulfinyl, ethylsulfinyl or propylsulfinyl group.
The xe2x80x9clower alkylsulfonyl groupxe2x80x9d in the definition of xe2x80x9cSubstituent group xcex1xe2x80x9d; and the xe2x80x9clower alkylsulfonyl groupxe2x80x9d of the xe2x80x9clower alkylsulfonyl group substituted with at least one group selected from Substituent group xcex1xe2x80x9d in the definition of R7 and R8 represent a group in which a sulfonyl (xe2x80x94SO2xe2x80x94) moiety is attached to the above xe2x80x9clower alkylxe2x80x9d group, preferably a straight or branched alkylsulfonyl group having from 1 to 4 carbon atoms, more preferably a methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or butylsulfonyl group, particularly preferably a methylsulfonyl, ethylsulfonyl or propylsulfonyl group.
The xe2x80x9cnon-aromatic hydrocarbon ringxe2x80x9d which is formed by R7 and R8, together with the carbon atom(s) to which they are attached; the xe2x80x9cnon-aromatic hydrocarbon ringxe2x80x9d of the xe2x80x9cnon-aromatic hydrocarbon ring substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2xe2x80x9d which is formed by R7 and R8, together with the carbon atom(s) to which they are attached; the xe2x80x9cnon-aromatic hydrocarbon ringxe2x80x9d which is formed by R11 and R12, together with the carbon atom(s) to which they are attached; and the xe2x80x9cnon-aromatic hydrocarbon ringxe2x80x9d of the xe2x80x9cnon-aromatic hydrocarbon ring substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2xe2x80x9d which is formed by R11 and R12, together with the carbon atom(s) to which they are attached, represent a saturated hydrocarbon ring having from 3 to 7 carbon atoms such as a cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring and cycloheptane ring or an unsaturated hydrocarbon ring having from 3 to 7 carbon atoms such as a cyclopropene ring, cyclobutene ring, cyclopentene ring, cyclohexene ring and cycloheptene ring, preferably a saturated hydrocarbon ring having 5 or 6 carbon atoms or an unsaturated hydrocarbon ring having 5 or 6 carbon atoms, more preferably an unsaturated hydrocarbon ring having 5 or 6 carbon atoms.
In the above formulae (II) and (III), since a double bond exists between the carbon atom to which R7 is attached and the carbon atom to which R8 is attached, R7 and R8, together with a carbon atom to which they are attached, do not form a saturated hydrocarbon ring.
The xe2x80x9cnon-aromatic heterocyclexe2x80x9d which is formed by R7 and R8, together with the carbon atom(s) to which they are attached; the xe2x80x9cnon-aromatic heterocyclexe2x80x9d of the xe2x80x9cnon-aromatic heterocycle substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2xe2x80x9d which is formed by R7 and R8, together with the carbon atom(s) to which they are attached; the xe2x80x9cnon-aromatic heterocyclexe2x80x9d which is formed by R11 and R12, together with the carbon atom(s) to which they are attached; and the xe2x80x9cnon-aromatic heterocyclexe2x80x9d of the xe2x80x9cnon-aromatic heterocycle substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2xe2x80x9d which is formed by R11 and R12, together with the carbon atom(s) to which they are attached, represent a 5- to 7-membered saturated heterocycle or partially saturated heterocycle containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, preferably a 5- or 6-membered saturated heterocycle or partially saturated heterocycle containing one or two sulfur atoms, oxygen atoms and/or nitrogen atoms, and examples of such a ring include for example a dithiolane ring, dioxane ring and pyrrolidine ring.
The xe2x80x9caryl ringxe2x80x9d which is formed by R7 and R8, together with the carbon atom(s) to which they are attached; and the xe2x80x9caryl ringxe2x80x9d of the xe2x80x9caryl ring substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2xe2x80x9d which is formed by R7 and R8, together with the carbon atom(s) to which they are attached, represent an aromatic hydrocarbon ring having from 6 to 10 carbon atoms such as a benzene ring and a naphthalene ring, preferably a benzene ring or a naphthalene ring, particularly preferably the benzene ring.
The above xe2x80x9caryl ringxe2x80x9d may be fused with a cycloalkyl group having from 3 to 10 carbon atoms and such fused rings include an indane ring.
The xe2x80x9cheteroaryl ringxe2x80x9d which is formed by R7 and R8, together with the carbon atom(s) atom to which they are attached; and the xe2x80x9cheteroaryl ringxe2x80x9d of the xe2x80x9cheteroaryl ring substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2xe2x80x9d which is formed by R7 and R8, together with the carbon atom(s) to which they are attached represent a 5- to 7-membered aromatic heterocycle containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and examples of such a ring include a furan ring, a thiophene ring, a pyrrole ring, an azepine ring, a pyrazole ring, an imidazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, a 1,2,3-oxadiazole ring, a triazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring and a pyrazine ring, preferably a 5- or 6-membered aromatic heterocycle containing one or two sulfur atoms, oxygen atoms and/or nitrogen atoms, more preferably a thiophene ring, an imidazole ring, a pyridine ring and a pyrazine ring.
The above xe2x80x9cheteroaryl ringxe2x80x9d may be fused with an other cyclic group, and examples of such a fused ring include an indole ring, a benzofuran ring, a benzothiophene ring, an isoquinoline ring and a quinoline ring.
Specific examples of the xe2x80x9cgroup of formula (II), (III) or (IV)xe2x80x9d in the definition of R6 preferably include: 
The xe2x80x9calkenyl groupxe2x80x9d and the xe2x80x9calkenyl groupxe2x80x9d of the xe2x80x9calkenyl group substituted with at least one group selected from Substituent group xcex1xe2x80x9d in the definition of R3 represent a straight or branched alkenyl group having from 3 to 10 carbon atoms, preferably a straight or branched alkenyl group having from 3 to 6 carbon atoms such as allyl, 2-butenyl, 3-butenyl, 2-methylallyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 5-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl groups, more preferably a straight or branched alkenyl group having 3 or 4 carbon atoms, particularly preferably an allyl or 2-butenyl group.
The xe2x80x9calkynyl groupxe2x80x9d and the xe2x80x9calkynyl groupxe2x80x9d of the xe2x80x9calkynyl group substituted with at least one group selected from Substituent group xcex1xe2x80x9d in the definition of R3 represent a straight or branched alkynyl group having from 3 to 10 carbon atoms, preferably a straight or branched alkynyl group having from 3 to 6 carbon atoms such as propargyl, 2-butynyl, 3-butynyl, 2-methyl-3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl groups, more preferably a straight or branched alkynyl group having 3 or 4 carbon atoms, particularly preferably a propargyl or 2-butynyl group.
The xe2x80x9carylene groupxe2x80x9d and the xe2x80x9carylene groupxe2x80x9d of the xe2x80x9carylene group substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2xe2x80x9d in the definition of R4 represent a divalent aromatic hydrocarbon ring having from 6 to 10 carbon atoms such as phenylene and naphthylene, preferably a phenylene group, particularly preferably a p-phenylene group.
The above xe2x80x9carylene groupxe2x80x9d may be fused with a cycloalkyl group having from 3 to 10 carbon atoms, and examples of such a group include an indan-4,7-di-yl group.
The xe2x80x9cheteroarylene groupxe2x80x9d and the xe2x80x9cheteroarylene groupxe2x80x9d of the xe2x80x9cheteroarylene group substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2xe2x80x9d in the definition of R4 represent a divalent 5- to 7-membered aromatic heterocyclic ring containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and examples thereof include furanylene, thienylene, pyrrolylene, azepinylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, 1,2,3-oxadiazolylene, triazolylene, thiadiazolylene, pyridylene, pyridazinylene, pyrimidinylene and pyrazinylene groups. Preferably, it represents a 5- or 6-membered aromatic heterocycle containing one or two sulfur atoms, oxygen atoms or/and nitrogen atoms, more preferably the thienylene, imidazolylene, pyridylene or pyrazinylene group, particularly preferably a thienylene group.
The above xe2x80x9cheteroarylene groupxe2x80x9d may be fused with other cyclic groups, and examples of such a fused ring include indole-4,7-diyl and benzothiophene-4,7-diyl.
The xe2x80x9caryl groupxe2x80x9d in the definition of R5 and xe2x80x9cSubstituent group xcex1xe2x80x9d; the xe2x80x9caryl groupxe2x80x9d of the xe2x80x9caryl group substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2xe2x80x9d in the definition of R5; and the xe2x80x9caryl groupxe2x80x9d of the xe2x80x9caryl group substituted with at least one group selected from Substituent group xcex3xe2x80x9d in the definition of xe2x80x9cSubstituent group xcex1xe2x80x9d represent a monovalent aromatic hydrocarbon ring having from 6 to 10 carbon atoms such as phenyl and naphthyl, more preferably a phenyl group.
The above xe2x80x9caryl groupxe2x80x9d may be fused with a cycloalkyl group having from 3 to 10 carbon atoms, and examples of such a group include 5-indanyl.
The xe2x80x9cheteroaryl groupxe2x80x9d in the definition of R5 and xe2x80x9cSubstituent group xcex1xe2x80x9d; the xe2x80x9cheteroaryl groupxe2x80x9d of the xe2x80x9cheteroaryl group substituted with at least one group selected from Substituent group xcex1 and Substituent group xcex2xe2x80x9d in the definition of R5; and the xe2x80x9cheteroaryl groupxe2x80x9d of the xe2x80x9cheteroaryl group substituted with at least one group selected from Substituent group xcex3xe2x80x9d in the definition of xe2x80x9cSubstituent group xcex1xe2x80x9d represent a monovalent 5- to 7-membered aromatic heterocyclic group containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms and include furanyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups. Preferably, it represents a monovalent 5- or 6-membered aromatic heterocyclic group containing one or two sulfur atoms, oxygen atoms and/or nitrogen atoms, more preferably a thienyl, imidazolyl, pyridyl or pyrazinyl group, and particularly preferably a thienyl or pyridyl group.
The above heteroaryl group may be fused with an other cyclic group, and examples of such fused rings include indolyl, benzofuranyl, benzothienyl, isoquinolyl and quinolyl groups.
The xe2x80x9chalogen atomxe2x80x9d in the definition of xe2x80x9cSubstituent group xcex1xe2x80x9d and xe2x80x9cSubstituent group xcex3xe2x80x9d includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
The xe2x80x9chalogeno lower alkoxy groupxe2x80x9d in the definition of xe2x80x9cSubstituent group xcex1xe2x80x9d and xe2x80x9cSubstituent group xcex3xe2x80x9d represents a group in which a xe2x80x9chalogeno lower alkyl groupxe2x80x9d described below is attached to an oxygen atom and, particularly preferably, it is a difluoromethoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy group.
The xe2x80x9clower alkanoyl groupxe2x80x9d in the definition of xe2x80x9cSubstituent group xcex1xe2x80x9d represents a formyl group or a group in which a carbonyl group is attached to the above xe2x80x9clower alkyl groupxe2x80x9d. Preferably, it is a straight or branched alkanoyl group having from 1 to 4 carbon atoms, more preferably a formyl, acetyl, propionyl, butyryl or isobutyryl group, still more preferably a formyl, acetyl or propionyl group, and particularly preferably a formyl or acetyl group.
The xe2x80x9chalogeno lower alkylthio groupxe2x80x9d in the definition of xe2x80x9cSubstituent group xcex1xe2x80x9d and xe2x80x9cSubstituent group xcex3xe2x80x9d represents a group in which a xe2x80x9chalogeno lower alkyl groupxe2x80x9d described below is attached to a sulfur atom. Particularly preferably, it is a difluoromethylthio, trifluoromethylthio or 2,2,2-trifluoroethylthio group.
The xe2x80x9cmono-lower alkylamino groupxe2x80x9d in the definition of xe2x80x9cSubstituent group xcex1xe2x80x9d represents a group in which one hydrogen atom of a xe2x80x94NH2 group is substituted with the above xe2x80x9clower alkyl groupxe2x80x9d. Preferably, it is a straight or branched monoalkylamino group having from 1 to 4 carbon atoms, more preferably a methylamino, ethylamino, propylamino, isopropylamino or butylamino group, particularly preferably a methylamino, ethylamino or propylamino group.
The xe2x80x9cdi(lower alkyl)amino groupxe2x80x9d in the definition of xe2x80x9cSubstituent group xcex1xe2x80x9d represents a group in which the two hydrogen atoms of a xe2x80x94NH2 group are substituted with the above xe2x80x9clower alkyl groupxe2x80x9d which may be the same or different. Preferably, it is a dialkylamino group in which any two alkyl groups are a straight or branched alkyl group having from 1 to 4 carbon atoms, more preferably a dimethylamino, ethylmethylamino, methylpropylamino, isopropylmethylamino, butylmethylamino, diethylamino or diisopropylamino group, particularly preferably a dimethylamino, ethylmethylamino or diethylamino group.
The xe2x80x9caryloxy groupxe2x80x9d and the xe2x80x9caryloxy groupxe2x80x9d of the xe2x80x9caryloxy group substituted with at least one group selected from Substituent group xcex3xe2x80x9d in the definition of xe2x80x9cSubstituent group xcex1xe2x80x9d represent a group in which the above xe2x80x9caryl groupxe2x80x9d is attached to an oxygen atom.
The xe2x80x9cheteroaryloxy groupxe2x80x9d and the xe2x80x9cheteroaryloxy groupxe2x80x9d of the xe2x80x9cheteroaryloxy group substituted with at least one group selected from Substituent group xcex3xe2x80x9d in the definition of the xe2x80x9csubstituent group xcex1xe2x80x9d represent a group in which the above xe2x80x9cheteroaryl groupxe2x80x9d is attached to an oxygen atom.
The xe2x80x9carylthio groupxe2x80x9d and the xe2x80x9carylthio groupxe2x80x9d of the xe2x80x9carylthio group substituted with at least one group selected from Substituent group xcex3xe2x80x9d in the definition of xe2x80x9cSubstituent group xcex1xe2x80x9d represent a group in which the above xe2x80x9caryl groupxe2x80x9d is attached to a sulfur atom.
The xe2x80x9cheteroarylthio groupxe2x80x9d and the xe2x80x9cheteroarylthio groupxe2x80x9d of the xe2x80x9cheteroarylthio group substituted with at least one group selected from xe2x80x9cSubstituent group xcex3xe2x80x9d in the definition of xe2x80x9cSubstituent group xcex1xe2x80x9d represent a group in which the above xe2x80x9cheteroaryl groupxe2x80x9d is attached to a sulfur atom.
The xe2x80x9chalogeno lower alkyl groupxe2x80x9d in the definition of xe2x80x9cSubstituent group xe2x80x9d and xe2x80x9cSubstituent group xcex3xe2x80x9d represents a group in which one or two or more hydrogen atoms of the above xe2x80x9clower alkyl groupxe2x80x9d is substituted with the above xe2x80x9chalogen atomxe2x80x9d. Preferably, it is a halogeno lower alkyl group having from 1 to 4 carbon atoms, more preferably a trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl or 2,2-dibromoethyl group, particularly preferably a trifluoromethyl, trichloromethyl, difluoromethyl or fluoromethyl group.
Since the compound (I) of the present invention can be converted to an ester, the xe2x80x9cesterxe2x80x9d means such an ester and includes an xe2x80x9cester of a hydroxyl groupxe2x80x9d and an xe2x80x9cester of a carboxyl groupxe2x80x9d, and includes an ester in which each ester residue is a xe2x80x9cgeneral protecting groupxe2x80x9d or a xe2x80x9cprotecting group removable by a biological method such as hydrolysis in vivoxe2x80x9d.
The xe2x80x9cgeneral protecting groupxe2x80x9d means a protecting group removable according to a chemical method such as hydrogenolysis, hydrolysis, electrolysis and photolysis.
Preferred examples of the xe2x80x9cgeneral protecting groupxe2x80x9d for the xe2x80x9cester of the hydroxyl groupxe2x80x9d include xe2x80x9caliphatic acyl groupsxe2x80x9d, for example, alkylcarbonyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, isovaleryl, octanoyl, nonylcarbonyl, decylcarbonyl, 3-methylnonylcarbonyl, 8-methylnonylcarbonyl, 3-ethyloctylcarbonyl, 3,7-dimethyloctylcarbonyl, undecylcarbonyl, dodecylcarbonyl, tridecylcarbonyl, tetradecylcarbonyl, pentadecylcarbonyl, hexadecylcarbonyl, 1-methylpentadecylcarbonyl, 14-methylpentadecylcarbonyl, 13,13-dimethyltetradecylcarbonyl, heptadecylcarbonyl, 15-methylhexadecylcarbonyl, octadecylcarbonyl, 1-methylheptadecylcarbonyl, nonadecylcarbonyl, eicosylcarbonyl and heneicosylcarbonyl groups, halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl groups, lower alkoxyalkylcarbonyl groups such as methoxyacetyl groups and unsaturated alkylcarbonyl groups such as acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl and (E)-2-methyl-2-butenoyl groups, (of which, a lower aliphatic acyl group having 1 to 6 carbon atoms is preferred); xe2x80x9caromatic acyl groupsxe2x80x9d, for example, arylcarbonyl groups such as benzoyl, xcex1-naphthoyl and xcex2-naphthoyl groups, halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl groups, lower alkylated arylcarbonyl groups such as 2,4,6-trimethylbenzoyl and 4-toluoyl groups, lower alkoxylated arylcarbonyl groups such as 4-anisoyl groups, nitrated arylcarbonyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl groups, lower alkoxycarbonylated arylcarbonyl groups such as 2-(methoxycarbonyl)benzoyl groups and arylated arylcarbonyl groups such as 4-phenylbenzoyl groups; xe2x80x9calkoxycarbonyl groupsxe2x80x9d such as lower alkoxycarbonyl groups, e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl groups, and lower alkoxycarbonyl groups substituted with halogen atoms or a tri(lower alkyl)silyl group, e.g., 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; the xe2x80x9cgeneral protecting groupxe2x80x9d for a hydroxy group also includes ethers including xe2x80x9ctetrahydropyranyl or tetrahydrothiopyranyl groupsxe2x80x9d such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl groups, tetrahydrothiopyran-2-yl and 4-methoxytetrahydrothiopyran-4-yl groups; xe2x80x9ctetrahydrofuranyl or tetrahydrothiofuranyl groupsxe2x80x9d such as tetrahydrofuran-2-yl groups and tetrahydrothiofuran-2-yl groups; xe2x80x9csilyl groupsxe2x80x9d, for example, tri(lower alkyl)silyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyl-di-t-butylsilyl and triisopropylsilyl groups, and tri(lower alkyl)silyl groups in which 1 or 2 alkyl groups are substituted by 1 or 2 aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl groups; xe2x80x9calkoxymethyl groupsxe2x80x9d, for example, lower alkoxymethyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl groups, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl groups and lower halogeno alkoxymethyl groups such as 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl groups; xe2x80x9csubstituted ethyl groupsxe2x80x9d, for example, lower alkoxylated ethyl groups such as 1-ethoxyethyl and 1-(isopropoxy)ethyl groups and halogenated ethyl groups such as 2,2,2-trichloroethyl groups; xe2x80x9caralkyl groupsxe2x80x9d, for example, lower alkyl groups substituted with 1 to 3 aryl groups such as benzyl, xcex1-naphthylmethyl, xcex2-naphthylmethyl, diphenylmethyl, triphenylmethyl, xcex1-naphthyldiphenylmethyl and 9-anthrylmethyl groups and lower alkyl groups substituted with 1 to 3 aryl groups each having an aryl ring substituted with a lower alkyl, lower alkoxy, nitro, halogen orcyano group, for example, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl groups; xe2x80x9calkenyloxycarbonyl groupsxe2x80x9d such as vinyloxycarbonyl and allyloxycarbonyl groups; and xe2x80x9caralkyloxycarbonyl groupsxe2x80x9d having an aryl ring which may be substituted with one or two lower alkoxy or nitro groups such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxy-benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl groups.
Preferred examples of the xe2x80x9cgeneral protecting groupxe2x80x9d relating to an xe2x80x9cester of a carboxyl groupxe2x80x9d include the above-mentioned xe2x80x9clower alkyl groupsxe2x80x9d; lower alkenyl groups such as ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl groups and 5-hexenyl groups; lower alkynyl groups such as ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl groups; the above-mentioned xe2x80x9chalogeno lower alkyl groupsxe2x80x9d; hydroxy xe2x80x9clower alkyl groupsxe2x80x9d such as 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl and 4-hydroxybutyl groups; xe2x80x9clower aliphatic acylxe2x80x9d-xe2x80x9clower alkyl groupsxe2x80x9d such as acetyl methyl; the above-mentioned xe2x80x9caralkyl groupsxe2x80x9d; and the above-mentioned xe2x80x9csilyl groupsxe2x80x9d.
The xe2x80x9cprotecting group removable by a biological method such as hydrolysis in vivoxe2x80x9d means a group which is removable through a biological method such as hydrolysis in the human body to give a free acid compound or a salt thereof. Whether a compound is such a derivative or not can be determined as follows: the compound is intravenously administered to an experimental animal such as a rat or mouse and the body fluid of the animal is thereafter studied. If the original compound or a pharmacologically acceptable salt thereof can be detected from the body fluid, the compound thus studied is judged as a derivative.
Preferred examples of the xe2x80x9cprotecting group which can be cleaved through a biological method such as hydrolysis in vivoxe2x80x9d for a hydroxy group include xe2x80x9ccarbonyloxyalkyl groupsxe2x80x9d such as 1-(acyloxy)xe2x80x9clower alkyl groupsxe2x80x9d including 1-(xe2x80x9clower aliphatic acylxe2x80x9doxy)xe2x80x9clower alkyl groupsxe2x80x9d, e.g. formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethy, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl and 1-pivaloyloxyhexyl groups, 1-(xe2x80x9ccycloalkylxe2x80x9dcarbonyloxy)xe2x80x9clower alkyl groupsxe2x80x9d, e.g. cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl and 1-cyclohexylcarbonyloxybutyl groups; 1-(xe2x80x9caromatic acylxe2x80x9doxy)xe2x80x9clower alkyl groupsxe2x80x9d, e.g. benzoyloxymethyl goups; (lower alkoxycarbonyloxy)alkyl groups, e.g. methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxym ethyl, cyclohexyloxycarbonyloxy(cyclohexyl)methyl, 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)ethyl, 1-(tert-butoxycarbonyloxy)ethyl, 1-(pentyloxycarbonyloxy)ethyl, 1-(hexyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propyl, 1-(cyclohexyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl, 1-(cyclohexyloxycarbonyloxy)butyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)propyl, 2-(methoxycarbonyloxy)ethyl, 2-(ethoxycarbonyloxy)ethyl, 2-(propoxycarbonyloxy)ethyl, 2-(isopropoxycarbonyloxy)ethyl, 2-(butoxycarbonyloxy)ethyl, 2-(isobutoxycarbonyloxy)ethyl, 2-(pentyloxycarbonyloxy)ethyl, 2-(hexyloxycarbonyloxy)ethyl, 1-(methoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)propyl, 1-(isopropoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)propyl, 1-(isobutoxycarbonyloxy)propyl, 1-(pentyloxycarbonyloxy)propyl, 1-(hexyloxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)butyl, 1-(propoxycarbonyloxy)butyl, 1-(isopropoxycarbonyloxy)butyl, 1-(butoxycarbonyloxy)butyl, 1-(isobutoxycarbonyloxy)butyl, 1-(methoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl and 1-(ethoxycarbonyloxy)hexyl groups; oxodioxolenylmethyl groups, e.g (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, (2-oxo-1,3-dioxolen-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl and (5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl groups; and the like; xe2x80x9cphthalidyl groupsxe2x80x9d, e.g. phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl groups; the above-mentioned xe2x80x9clower aliphatic acyl groupsxe2x80x9d; the above-mentioned xe2x80x9caromatic acyl groupsxe2x80x9d; xe2x80x9chalf-ester salt residues of succinic acidxe2x80x9d; xe2x80x9cphosphate ester salt residuesxe2x80x9d; xe2x80x9cester-forming residues of an amino acid or the likexe2x80x9d; carbamoyl groups; carbamoyl groups substituted with 1 or 2 lower alkyl groups; and xe2x80x9c1-(acyloxy)alkyloxycarbonyl groups, e.g. pivaloyloxymethyloxycarbonyl.
Preferred examples of the xe2x80x9cprotecting group removable by a biological method such as hydrolysis in vivoxe2x80x9d for a carboxyl group include xe2x80x9calkoxy lower alkyl groupsxe2x80x9d such as lower alkoxy lower alkyl groups, e.g. methoxyethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl, ethoxymethyl, n-propoxymethyl, isoproxymethyl, n-butoxymethyl or tert-butoxymethyl groups (lower alkoxy lower alkoxy)alkyl groups such as 2-methoxyethoxymethyl groups; lower alkoxylated lower alkoxy lower alkyl groups, e.g. 2-methoxyethoxymethyl groups, xe2x80x9carylxe2x80x9doxyxe2x80x9clower alkyl groupsxe2x80x9d, e.g. phenoxymethyl groups, and halogeno lower alkoxy lower alkyl groups, e.g. 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl groups; xe2x80x9cxe2x80x9clower alkoxyxe2x80x9dcarbonylxe2x80x9clower alkyl groupsxe2x80x9dxe2x80x9d, e.g. methoxycarbonyl groups; xe2x80x9ccyanoxe2x80x9clower alkyl groupsxe2x80x9dxe2x80x9d e.g. cyanomethyl or 2-cyanomethyl groups; xe2x80x9cxe2x80x9clower alkylxe2x80x9dthiomethyl groupsxe2x80x9d, e.g. methylthiomethyl or ethylthiomethyl groups; xe2x80x9cxe2x80x9carylxe2x80x9dthiomethyl groupsxe2x80x9d, e.g. phenylthiomethyl or naphthylthiomethyl groups; xe2x80x9cxe2x80x9clower alkylxe2x80x9dsulfonylxe2x80x9clower alkyl groups optionally substituted with halogen atomsxe2x80x9dxe2x80x9d, e.g. 2-methanesulfonylethyl or 2-trifluoromethanesulfonylethyl groups; xe2x80x9cxe2x80x9carylxe2x80x9dsulfonylxe2x80x9clower alkyl groupsxe2x80x9d, e.g. 2-benzenesulfonylethyl or 2-toluenesulfonylethyl groups; the above-mentioned xe2x80x9c1-(acyloxy)xe2x80x9dlower alkyl groupsxe2x80x9dxe2x80x9d; the above-mentioned xe2x80x9cphthalidyl groupsxe2x80x9d; the above-mentioned xe2x80x9caryl groupsxe2x80x9d; the above-mentioned xe2x80x9clower alkyl groupsxe2x80x9d; xe2x80x9ccarboxy alkyl groupsxe2x80x9d, e.g. carboxymethyl groups; and xe2x80x9camide-forming residues of an amino acidxe2x80x9d, e.g. phenylalanine groups.
In the case where the compound (I) of the present invention has a basic group such as an amino group, the compound can be converted to a salt by reacting it with an acid and in the case where the compound (I) has an acidic group such as a carboxyl group, the compound can be converted to the salt by reacting it with a base; the xe2x80x9cpharmacologically acceptable salt thereofxe2x80x9d means such salts.
Preferred examples of the salt based on the basic group include inorganic acid salts such as a hydrohalogenated acid salts, e.g., hydrofluoride, hydrochloride, hydrobromide and hydroiodide salts, nitrates, perchlorates, sulfates and phosphates; organic acid salts such as a lower alkanesulfonate, e.g., methanesulfonate, trifluoromethanesulfonate and ethanesulfonate salts, arylsulfonate, e.g., benzenesulfonate and p-toluenesulfonate salts, acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates and maleates; and amino acid salts such as glycine salts, lysine salts, arginates, omithine salts, glutamates and aspartates.
Whereas, preferred examples of the salt based on the acidic group include metal salts such as an alkali metal salt, e.g., sodium salts, potassium salts and lithium salts, an alkali earth metal salt, e.g., calcium salts and magnesium salts, aluminum salts and iron salts; amine salts such as inorganic salts, e.g., ammonium salts and organic salts, e.g., t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycinealkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,Nxe2x80x2-dibenzylethylenediamine salts, chloroprocain salts, procain salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts and tris(hydroxymethyl)aminomethane salts; and amino acid salts such as glycine salts, lysine salts, arginates, omithine salts, glutaminates and aspartates.
Since the compound (I) of the present invention can be converted to a derivative other than the above-mentioned xe2x80x9cpharmaceutically acceptable saltxe2x80x9d and the above-mentioned xe2x80x9cesterxe2x80x9d when it has an amino group and/or carboxy group, the xe2x80x9cother derivativexe2x80x9d means such a derivative. Examples of such a derivative include amide derivatives.
The compounds of formula (I) of the present invention sometimes absorb moisture when they are left to stand in the atmosphere or crystallized so that they carry adsorbed water and are thus hydrated. Such hydrates are also included in the present invention and included in the term xe2x80x9ccompound of the formula (I)xe2x80x9d and species thereof.
Since the compound of the formula (I) has an asymmetric carbon atom in the molecule thereof, it has various isomers. In the compound of the present invention, these isomers and mixtures of these isomers are shown by a single formula, i.e., the formula (I). Accordingly, the present invention includes all of these isomers and the mixtures of these isomers.
Specific examples of the compounds of the formula (I) of the present invention include the compounds described in the following Table 1 to Table 9.
In the above tables, xe2x80x9cMexe2x80x9d means methyl, xe2x80x9cEtxe2x80x9d means ethyl, xe2x80x9cPrxe2x80x9d means propyl, xe2x80x9ci-Prxe2x80x9d means isopropyl, xe2x80x9cc-Prxe2x80x9d means cyclopropyl, xe2x80x9cBuxe2x80x9d means butyl, xe2x80x9cs-Buxe2x80x9d means s-butyl, xe2x80x9ci-Buxe2x80x9d means isobutyl, xe2x80x9ct-Buxe2x80x9d means t-butyl, xe2x80x9cc-Pnxe2x80x9d means cyclopentyl, xe2x80x9cc-Hxxe2x80x9d means cyclohexyl, xe2x80x9cPhxe2x80x9d means phenyl, xe2x80x9cPyxe2x80x9d means pyridyl, xe2x80x9cThiexe2x80x9d means thienyl, and xe2x80x9cBnxe2x80x9d means benzyl. In addition, xe2x80x9csub.1xe2x80x9d to xe2x80x9csub.51xe2x80x9d in table 5 above signify the following substituents respectively.
In the above tables, compounds of formula (I) in which R1 is hydroxyamino group are illustrated. The present invention, however, also encompasses hydroxy derivatives [which are compounds of formula (I) wherein R1 is a hydroxy group], corresponding to the above compounds as specific examples.
In the tables preferred compounds are those of compound numbers 1-1 to 1-4, 1-8 to 1-11, 1-24 to 1-27, 1-40 to 1-43, 1-56 to 1-59, 1-68 to 1-75, 1-88 to 1-91, 1-104 to 1-107, 1-1-121, 1-137, 1-153, 1-180 to 1-189, 2-1 to 2-4, 2-8 to 2-11, 2-24 to 2-27, 2-40 to 2-43, 2-56 to 2-59, 2-68 to 2-75, 2-88 to 2-91, 2-104 to 2-107, 2-121, 2-137, 2-153, 2-180 to 2-189, 3-1 to 3-5, 3-7 to 3-12, 3-25 to 3-28, 3-41 to 3-44, 3-57 to 3-60, 3-69 to 3-76, 3-89 to 3-92, 3-105 to 3-108, 3-122, 3-136, 3-138, 3-154, 3-169, 3-171, 3-172, 3-181 to 3-192, 4-1 to 4-4, 4-8 to 4-11, 4-24 to 4-27, 4-40 to 4-43, 4-56 to 4-59, 4-68 to 4-75, 4-88 to 4-91, 4-104 to 4-107, 4-121, 4-137, 4-153, 4-180 to 4-189, 5-1 to 5-91, 5-98, 5-99, 6-4, 6-10 to 6-12, 6-22 to 6-27, 7-9 to 7-12, 7-14, 7-16, 7-25 to 7-28, 7-30, 7-32, 7-41 to 7-44, 7-46, 7-48, 7-57 to 7-60, 7-62, 7-64, 7-69 to 7-76, 7-89 to 7-92, 7-94, 7-96, 7-105 to 7-108, 7-121 to 7-123, 7-136 to 7-139, 7-153 to 7-155, 7-172, 7-181 to 7-183, 7-185 to 7-187, 7-190, 7-194 to 7-197, 7-206 to 7-208, 7-211 to 7-214, 7-217 to 7-221, 8-9 to 8-12, 8-14, 8-16, 8-25 to 8-28, 8-30, 8-32, 8-41 to 8-44, 8-46, 8-48, 8-57 to 8-60, 8-62, 8-64, 8-69 to 8-76, 8-89 to 8-92, 8-94, 8-96, 8-105 to 8-108, 8-121 to 8-123, 8-136 to 8-139, 8-153 to 8-155, 8-172, 8-181 to 8-183, 8-185 to 8-187, 8-190, 8-194 to 8-197, 8-206 to 8-208, 8-211 to 8-214, 8-217 to 8-221, 9-3, 9-9, 9-11 to 9-19, 9-22, 9-28, 9-30 to 9-38, 9-41, 9-47, 9-49 to 9-57, 9-60, 9-66, 9-68 to 9-76, 9-79, 9-85, 9-87 to 9-95, 9-98, 9-104, 9-106 to 9-114, 9-117, 9-123, 9-125 to 9-133, 9-136, 9-142 and 9-144 to 9-152;
more preferred compounds are those of compound numbers 1-2, 1-9, 1-10, 1-25, 1-26, 1-41, 1-42, 1-57, 1-58, 1-69, 1-70, 1-73, 1-74, 1-89, 1-90, 1-105, 1-137, 1-153, 1-180 to 1-189, 2-2, 2-9, 2-25, 2-26, 2-41, 2-57, 2-69, 2-73, 2-89, 2-105, 2-137, 2-153, 2-180, 2-181, 2-185, 2-186, 3-2, 3-7, 3-10, 3-11, 3-25 to 3-27, 3-42, 3-43, 3-58, 3-59, 3-70, 3-71, 3-374, 3-75, 3-90, 3-91, 3-106, 3-107, 3-122, 3-136, 3-138, 3-154, 3-169, 3-171, 3-172, 3-181 to 3-192, 4-2, 4-9, 4-10, 4-25, 4-26, 4-41, 4-42, 4-57, 4-58, 4-69, 4-70, 4-73, 4-74, 4-89, 4-90, 4-105, 4-137, 4-153, 4-180 to 4-189, 5-1, 5-2, 5-9, 5-10, 5-15 to 5-35, 5-37 to 5-40, 5-43 to 5-45, 5-68 to 5-71, 5-74 to 5-79, 5-98, 5-99, 7-25 to 7-27, 7-32, 7-41 to 7-43, 7-57 to 7-59, 7-64, 7-70, 7-73 to 7-75, 7-89 to 7-91, 7-96, 7-106, 7-122, 7-138, 7-154, 7-172, 7-181, 7-182, 7-185, 7-186, 7-194 to 7-197, 7-206 to 7-208, 7-211 to 7-214, 7-217 to 7-221, 8-25 to 8-27, 8-32, 8-41 to 8-43, 8-57 to 8-59, 8-64, 8-70, 8-73 to 8-75, 8-89 to 8-91, 8-96, 8-106, 8-122, 8-138, 8-154, 8-172, 8-181, 8-182, 8-185, 8-186, 8-194 to 8-197, 8-206 to 8-208, 8-211 to 8-214, 8-217 to 8-221, 9-12, 9-13, 9-15, 9-16, 9-18, 9-19, 9-31, 9-32, 9-34, 9-35, 9-37, 9-38, 9-50, 9-51, 9-53, 9-54, 9-56, 9-57, 9-69, 9-70, 9-72, 9-73, 9-75, 9-76, 9-88, 9-89, 9-91, 9-92, 9-94, 9-95, 9-107, 9-108, 9-110, 9-111, 9-113, 9-114, 9-126, 9-127, 9-129, 9-130, 9-132, 9-133, 9-145, 9-146, 9-148, 9-149, 9-151 and 9-152;
still more preferred compounds are those of compound numbers 1-9, 1-25, 1-41, 1-57, 1-69, 1-73, 1-89, 1-180 to 1-182, 1-185, 1-186, 2-25, 2-89, 3-10, 3-26, 3-42, 3-58, 3-70, 3-74, 3-90, 3-106, 3-181 to 183, 3-186, 3-187, 4-9, 4-25, 4-41, 4-57, 4-69, 4-73, 4-89, 4-180, 4-181, 4-185, 4-186, 5-15, 5-17, 5-18, 5-21 to 5-27, 5-29 to 5-35, 5-37 to 5-40, 5-44, 5-45, 5-68 to 5-71, 5-74 to 5-77, 5-84 to 5-91, 5-98, 5-99, 7-26, 7-42, 7-58, 7-74, 7-90, 7-181, 7-182, 7-194, 7-196, 7-212, 7-213, 7-217 to 7-221, 8-26, 8-42, 8-58, 8-74, 8-90, 8-181, 8-182, 8-194, 8-196, 8-212, 8-213 and 8-217 to 8-221.
The followings can be exemplified as particularly preferable compounds:
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)-2-(2-phthalimidoethyl)glycinamide (Compound No. 3-26),
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)-2-[2-(thiazolidin-2,4-dione-3-yl)ethyl]glycinamide (Compound No. 5-44),
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)-2-[2-(quinazolin-2,4-dione-3-yl)ethyl]glycinamide (Compound No. 1-25),
(xc2x1)-2-[2-(5-fluoropyrimidin-2,4-dione-3-yl)ethyl]-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide (Compound No. 5-31),
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)-2-[2-(thieno[3,2-d]pyrimidin-2,4-dione-3-yl)ethyl]glycinamide (Compound No. 5-23),
(xc2x1)-N-hydroxy-Nxcex1-methyl-2-[2-(7-methylxanthin-1-yl)ethyl]-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide (Compound No. 5-25),
(xc2x1)-N-hydroxv-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)-2-[2-pteridin-2,4-dione-3-yl)ethyl]glycinamide (Compound No. 5-21),
(xc2x1)-2-[2-(1,1-dioxo-1,2-benzisothiazol-3-one-2-yl)ethyl]-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide (Compound No. 2-25),
(xc2x1)-N-hydroxy-Nxcex1-methyl-2-[2-(6-methylpyrimidin-2,4-dione-3-yl)ethyl]-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide (Compound No. 5-39),
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)-2-[2-(5-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]glycinamide (Compound No. 5-37), N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)-2(R)-(2-phthalimidoethyl)glycinamide (Compound No. 3-26),
(xc2x1)-Nxcex1-[4-(4-fluorophenoxy)benzenesulfonyl]-N-hydroxy-Nxcex1-methyl-2-(2-phthalimidoethyl)glycinamide (Compound No. 3-182),
(xc2x1)-2-[2-(6-chloropyrimidin-2,4-dione-3-yl)ethyl]-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide (Compound No. 5-84),
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)-2-[2-(6-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]glycinamide (Compound No. 5-88),
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-[4-(pyridin-4-yl)oxybenzenesulfonyl]-2-[2-thieno[3,2-d]pyrimidin-2,4-dione-3-yl)ethyl]glycinamide (Compound No. 5-98),
(xc2x1)-2-[2-(6-chloro-1-methylpyrimidin-2,4-dione-3-yl)ethyl]-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide (Compound No. 7-212),
(xc2x1)-Nxcex1-[4-(4-chlorophenoxy)benzenesulfonyl]-2-[2-(6-chloropyrimidin-2,4-dione-3-yl)ethyl]-N-hydroxy-Nxcex1-methylglycinamide (Compound No. 7-181),
(xc2x1)-2-[2-(6-chloropyrimidin-2,4-dione-3-yl)ethyl-Nxcex1-[4-(4-fluorophenoxy)-benzenesulfonyl]-N-hydroxy-Nxcex1-methylglycinamide (Compound No. 7-182),
(xc2x1)-Nxcex1-[4-(4-chlorophenoxy)benzenesulfonyl]-N-hydroxy-Nxcex1-methyl-2-[2-(6-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]glycinamide (Compound No. 8-181),
(xc2x1)-Nxcex1-[4-(4-fluorophenoxy)benzenesulfonyl]-N-hydroxy-Nxcex1-methyl-2-[2-(6-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]glycinamide (Compound No. 8-182),
(xc2x1)-Nxcex1-[4-(3-chlorophenoxy)benzenesulfonyl]-N-hydroxy-Nxcex1-methyl-2-[2-(6-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]glycinamide (Compound No. 8-194),
(xc2x1)-Nxcex1-[4-(3-chlorophenoxy)benzenesulfonyl]-2-[2-(6-chloropyrimidin-2,4-dione-3-yl)ethyl]-N-hydroxy-Nxcex1-methylglycinamide (Compound No. 7-194),
(xc2x1)-2-[2-(6-chloropyrimidin-2,4-dione-3-yl)ethyl]-Nxcex1-ethyl-N-hydroxy-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide (Compound No. 7-42),
(xc2x1)-2-[2-(6-chloropyrimidin-2,4-dione-3-yl)ethyl]-Nxcex1-[4-(3-fluorophenoxy)-benzenesulfonyl]-N-hydroxy-Nxcex1-methylglycinamide (Compound No. 7-196),
(xc2x1)-2-[2-(6-chloropyrmidin-2,4-dione-3-yl)ethyl]-N-hydroxy-Nxcex1-methyl-Nxcex1-[4-(pyridin-4-yl)oxybenzenesulfonyl]glycinamide (Compound No. 7-26),
(xc2x1)-Nxcex1-[4-(3-fluorophenoxy)benzenesulfonyl]-N-hydroxy-Nxcex1-methyl-2-[2-(6-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]glycinamide (Compound No. 8-196),
(xc2x1)-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-(pyridin-4-yl)oxybenzenesulfonyl]-2-[2-(6-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]glycinamide (Compound No. 8-26),
(xc2x1)-Nxcex1-ethyl-N-hydroxy-Nxcex1-(4-phenoxybenzenesulfonyl)-2-[2-(6-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]glycinamide (Compound No. 8-42),
(xc2x1)-N-hydroxy-Nxcex1-methyl-2-[2-(1-methyl-6-trifluoromethylpyrimidin-2,4-dione-3-yl)ethyl]-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide (Compound No. 8-212),
(xc2x1)-2-[2-(5-chloropyrimidin-2,4-dione-3-yl)ethyl]-N-hydroxy-Nxcex1-methyl-Nxcex1-(4-phenoxybenzenesulfonyl)glycinamide (Compound No. 5-35),
Nxcex1-[4-(3-chlorophenoxy)benzenesulfonyl]-N-hydroxy-Nxcex1-methyl-2-[2-quinazolin-2,4-dione-3-yl)ethyl]glycinamide (Compound No. 1-182),
Nxcex1-[4-(3-chlorophenoxy)benzenesulfonyl]-N-hydroxy-Nxcex1-methyl-2-[2-(thieno[3,2-d]pyrimidin-2,4-dione-3-yl)ethyl]glycinamide (Compound No. 5-99), and
Nxcex1-[4-(3-chlorophenoxy)benzenesulfonyl]-N-hydroxy-Nxcex1-methyl-2-(2-phthalimidoethyl)glycinamide (Compound No. 3-183).
The compound of the formula (I) of the present invention can be prepared according to the following Method A to Method F. 
In the above formulae,
R2, R4 and R5 have the same meanings as defined above;
R3a represents a group from the definition of R3 other than the hydrogen atom;
G1 represents a carboxyl protecting group;
L represents a hydroxyl group or a leaving group; and
Q represents an above-mentioned xe2x80x9chalogen atomxe2x80x9d (preferably a bromine atom or a chlorine atom, most preferably a chlorine atom).
The xe2x80x9cleaving groupxe2x80x9d in the definition of L indicates a group which normally leaves as a nucleophilic residue, and examples of such a group include halogen atoms such as chlorine, bromine and iodine atoms; trihalogenomethyloxy groups such as trichloromethyloxy groups; lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy groups; halogeno lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy groups; and arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy and p-nitrobenzenesulfonyloxy groups, of which halogen atoms and lower alkanesulfonyloxy groups are preferred.
The xe2x80x9ccarboxyl protecting groupxe2x80x9d in the definition of G1 means a protecting group which can be removed by a chemical process such as hydrogenolysis, hydrolysis, electrolysis and photolysis, and examples of such a group include similar groups to those described as the xe2x80x9cgeneral protecting groupxe2x80x9d relating to an xe2x80x9cester of a carboxyl groupxe2x80x9d. Preferably, it is a xe2x80x9clower alkyl groupxe2x80x9d, a xe2x80x9clower alkenyl groupxe2x80x9d, an xe2x80x9caryl groupxe2x80x9d or an xe2x80x9caralkyl groupxe2x80x9d, and more preferred is a xe2x80x9clower alkyl groupxe2x80x9d, a xe2x80x9clower alkenyl groupxe2x80x9d or an xe2x80x9caralkyl groupxe2x80x9d.
Step 1 is a process to prepare the compound of formula (3) by reacting the amino group of the compound of formula (1) with the sulfonyl halide compound of formula (2), and the reaction is carried out in a solvent in the presence or absence of a base.
Examples of a solvent employable here include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; and aliphatic hydrocarbons such as pentane, hexane and heptane.
Examples of a base employable here include alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide; alkali metal hydrides such as sodium hydride and lithium hydride; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; and amines such as triethylamine, tributylamine, pyridine, picoline and 1,8-diazabicyclo[5.4.0]-7-undecene.
The reaction can be carried out at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably from 0xc2x0 C. to 100xc2x0 C.
While the reaction time varies mainly depending on the reaction temperature, the solvent used, etc., it is usually from 10 minutes to 48 hours, preferably from 30 minutes to 12 hours.
Step 2 is a process to prepare the compound of formula (Ia) of the present invention by removing the G1 group from the compound of formula (3), and the removal of the protecting group, which may be varied depending on the kind thereof, can be carried out according to methods generally known in the art as follows:
In the case where a lower alkyl group or an aryl group is used as the carboxyl protecting group, it can be removed by treatment with an acid or a base.
Examples of the acid include hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, and the base is not particularly limited, provided that it does not affect other parts of the compound, and preferred examples include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide or a conc. ammonia-methanol solution.
Incidentally, an isomerization may occur in hydrolysis with a base.
The solvent employable here is not particularly limited, provided that it is one usually used in hydrolysis reactions and does not inhibit the reaction, and preferred examples thereof include water or mixtures of water and an organic solvent such as an alcohol, e.g. methanol, ethanol or n-propanol, or an ether, e.g. tetrahydroftiran or dioxane.
While the reaction temperature and time vary depending on the starting material, the solvent, the reagent used, etc. and are not particularly limited, the reaction is usually carried out at a temperature of from 0xc2x0 C. to 150xc2x0 C. for the period of from 1 to 10 hours to control any side reactions.
In the case where the carboxyl protecting group is a diaryl-substituted methyl group such as diphenylmethyl, it can be usually removed by treatment with an acid in a solvent.
The solvent employable here is preferably an aromatic hydrocarbon such as anisole, and a fluorinated organic acid such as trifluoroacetic acid can be used as the acid employable here.
While the reaction temperature and time vary depending on the starting material, the solvent, the acid used, etc., the reaction is usually carried out at a room temperature for a period of from 30 minutes to 10 hours.
In the case where the carboxyl protecting group is an aralkyl group or a halogeno lower alkyl group, it can be usually removed by reduction in a solvent.
In the case where the carboxyl protecting group is a halogeno lower alkyl group, the reduction method is preferably a process of a chemical reduction such as zinc-acetic acid, and in the case where it is an aralkyl group, it can be carried out by a catalytic reduction with a catalyst such as palladium on carbon, palladium hydroxide or platinum or by a chemical reduction with an alkali metal sulfide such as potassium sulfide or sodium sulfide.
The solvent employable here is not particularly limited, provided that it does not affect the present reaction, and preferred examples thereof include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; aliphatic acids such as acetic acid or mixtures of these organic solvents and water.
While the reaction temperature and time vary depending on the starting material, the solvent, the reduction method, etc., the reaction is usually carried out at a temperature of from 0xc2x0 C. to a room temperature for a period of from 5 minutes to 12 hours.
In the case where the carboxyl protecting group is an alkoxymethyl group, it can be usually removed by treatment with an acid in a solvent.
The acid employable here is not particularly limited, provided that it is usually used as a Brxcfx86nsted acid, and preferred examples include inorganic acids such as hydrochloric acid and sulfuric acid and organic acids such as acetic acid and paratoluenesulfonic acid.
The solvent employable here is not particularly limited, provided that it does not affect the present reaction, and preferred examples include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane or mixtures of these organic solvents and water.
While the reaction temperature and time vary depending on the starting material, the solvent, the kind of the acid used, etc., the reaction is usually carried out at a temperature of from 0xc2x0 C. to 100xc2x0 C. for a period of from 10 minutes to 18 hours.
When the removal of the carboxyl protecting group is carried out by treatment with ammonia according to a conventional method, amidation can be effected.
If desired, alkyl metal salts can be prepared according to a conventional method by dissolving the above-mentioned carboxylic acid thus produced in a mixture of water and a water-immiscible organic solvent such as ethyl acetate, adding to this solution an aqueous alkali metal carbonate or bicarbonate solution such as an aqueous sodium hydrogencarbonate solution or a potassium carbonate solution at a temperature of 0xc2x0 C. to room temperature, then adjusting the pH of the mixture to approximately 7, and collecting the separated precipitates by filtering.
Further, esters re-protected with a carboxyl protecting group, which can be easily hydrolysed in vivo, can be prepared by reacting the salt thus prepared or the above-mentioned carboxylic acid with 2 equivalents of base (preferably an organic base such as triethylamine or dicyclohexylamine, a hydrogenated alkali metal salt such as sodium hydride or an alkali metal carbonate or bicarbonate such as sodium hydrogencarbonate, sodium carbonate or potassium carbonate) in a solvent (preferably an ether such as tetrahydrofuran or a polar solvent such as N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide and triethyl phosphate) and reacting an aliphatic acyloxymethyl halide such as acetoxymethyl chloride or propionyloxymethyl bromide, a 1-lower alkoxycarbonyloxyethyl halide such as 1-methoxycarbonyloxyethyl chloride or 1-ethoxycarbonyloxyethyl iodide, a phthalidyl halide or a (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl halide with the reaction mixure.
While the reaction temperature and time vary depending on the starting material, the solvent and the kind of the reagents, the reaction is usually carried out at a temperature of from 0xc2x0 C. to 100xc2x0 C. for a period of from 0.5 to 10 hours.
Step 3 is a process for hydroxyamidation of the compound of formula (Ia) of the present invention. The compound of formula (Ib) of the present invention is produced by reacting the compound of formula (Ia) or a reactive derivative thereof with hydroxylamine.
In the case where the compound (Ia) per se is subjected to hydroxyamidation in the present step, the reaction is carried out in the presence of a condensation agent such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or N,Nxe2x80x2-carbonyldiimidazole.
Examples of the solvent employable here include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, dilsopropyl ether, tetrahydrofaran and dioxane; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, s-butanol, isobutanol and t-butanol; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; and water or a mixture thereof.
The reaction may be carried out at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably from 0xc2x0 C. to 100xc2x0 C. The reaction time is usually for a period of from 10 minutes to 48 hours, preferably from 30 minutes to 12 hours.
In the case where the compound of formula (Ia) is converted into a reactive derivative first and, then, is subjected to hydroxyamidation, examples of the reactive derivative include acid halides, mixed acid anhydrides and activated esters.
The acid halides can be prepared by reacting the compound of formula (Ia) with a halogenating agent such as thionyl chloride or oxalyl chloride; the mixed acid anhydrides can be prepared by reacting the compound of formula (Ia) with an acid halide such as methyl chlorocarbonate or ethyl chlorocarbonate; and the activated esters can be prepared by reacting the compound of formula (Ia) with a hydroxy compound such as N-hydroxysuccinimide or N-hydroxyphthalimide in the presence of one of the condensation agent mentioned obove, and in each case reaction conditions usually employed in conventional organic synthetic chemistry are applied.
It is possible to prepare the compound of formula (Ib) by preparing a protected hydroxyamide using a protected hydroxylamine such as O-benzylhydroxylamine or O-(t-butyldimethylsilyl)hydroxylamine instead of hydroxylamine according to the present step and, then, by deprotecting it according to the method described in Step 2.
Step 4 is a process to prepare the compound of formula (5) by modifying the N atom in the sulfonamide moiety of the compound of formula (3).
a) In this step, if L of the compound of formula (4) is a hydroxyl group, the Mitsunobu reaction [D. L. Hughes, Org. React., 42, 335 (1992)] is applied.
The reagent employable in the Mitsunobu reaction is not particularly limited, provided that it can usually be used in the Mitsunobu reaction, and preferred examples nclude the combination of an azo compound such as a di-lower alkyl azodicarboxylate, e.g. diethyl azodicarboxylate or diisopropyl azodicarboxylate, or an azodicarbonyl, e.g. 1,1xe2x80x2-(azodicarbonyl)dipiperidine, and a phosphine such as a triarylphosphine, e.g. triphenylphosphine, or a tri-lower alkylphosphine such as tri-n-butylphosphine, the combination of the di-lower alkylazodicarboxylate and the triarylphosphine is more preferred, and the combination of diethyl azodicarboxylate and triphenylphosphine is most preferred.
The solvent employable here is not particularly limited, provided that it does not inhibit the reaction and dissolves the starting material to some extent, and preferred example include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide and sulfones such as sulfolane, of which the aromatic hydrocarbons and the ethers are preferred.
The reaction may be carried out at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably from 0xc2x0 C. to 100xc2x0 C.
While the reaction time varies mainly depending on the reaction temperature, the starting material, the reagent or the kind of the solvent used, it is usually for the period of from 10 minutes to 3 days, preferably from 30 minutes to 12 hours.
b) In the case where the group L of the compound of formula (4) is a leaving group, the reaction is carried out in a solvent in the presence or absence of a base.
Examples of the solvent employable here include alcohols such as methanol, ethanol, propanol and isopropanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; and aliphatic hydrocarbons such as pentane, hexane and heptane.
Examples of the base employable here include alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide; alkali metal hydrides such as sodium hydride and lithium hydride; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; and amines such as triethylamine, tributylamine, pyridine, picoline and 1,8-diazabicyclo[5.4.0]-7-undecene.
Step 5 is a process to prepare the compound of formula (Ic) of the present invention by removing the G1 group of the compound of formula (5) and is carried out in a similar manner to the procedure described in Step 2.
Step 6 is a process to prepare the compound of formula (Id) of the present invention by hydroxyamidation of the compound of formula (Ic) of the present invention and is carried out in a similar manner to the procedure described in Step 3.
 less than Process B greater than 
Process B is a process to prepare the compound of formula (1xe2x80x2), which is a compound of formula (1) in which R2 is a group of formula xe2x80x94Axe2x80x94R6 (in the formulae, A and R6 have the same meanings as defined above), which is a starting material in Method A. 
In the formulae,
R6, A, G1 and L have the same meanings as defined above; and
G2 represents an amino protecting group.
The xe2x80x9camino protecting groupxe2x80x9d in the definition of G2 means a protecting group which may be removed by a chemical process such as hydrogenolysis, hydrolysis, electrolysis and photolysis, and examples include the above-mentioned xe2x80x9caliphatic acyl groupsxe2x80x9d, the above-mentioned xe2x80x9caromatic acyl groupsxe2x80x9d, the above-mentioned xe2x80x9calkoxycarbonyl groupsxe2x80x9d, the above-mentioned xe2x80x9calkenyloxycarbonyl groupsxe2x80x9d, the above-mentioned xe2x80x9caralkyloxycarbonyl groupsxe2x80x9d, the above-mentioned xe2x80x9csilyl groupsxe2x80x9d and the above-mentioned xe2x80x9caralkyl groupsxe2x80x9d, of which the xe2x80x9calkoxycarbonyl groupsxe2x80x9d, the xe2x80x9calkenyloxycarbonyl groupsxe2x80x9d and the xe2x80x9caralkyloxycarbonyl groupsxe2x80x9d are preferred, and t-butoxycarbonyl, allyloxycarbonyl and benzyloxycarbonyl groups are more preferred.
Step 7 is a process to prepare the compound of formula (8) by reacting the compound of formula (6) with the compound of formula (7) and is carried out in a similar manner to procedures described in a) or b) of Step 4 above.
Step 8 is a process to prepare the compound of formula (1xe2x80x2) by removing the G2 group of the compound of formula (8).
The removal of the G2 group, which may be varied depending on its kind, can be carried out according to methods generally known in the art, which are described below:
In the case where G2 is a silyl group, it can be conventionally removed by treatment with a compound capable of producing a fluorine anion such as tetrabutylammonium fluoride.
The reaction solvent is not particularly limited, provided that it does not inhibit the reaction, and preferred examples include ethers such as tetrahydrofuran and dioxane.
The reaction temperature and time are not particularly limited and the reaction is usually carried out at room temperature for the period of from 10 to 18 hours.
In the case where G2 is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it can be removed by treatment with an acid or a base in the presence of an aqueous solvent.
The acid employable here is not particularly limited, provided that it is conventionally used and does not inhibit the reaction, and preferred examples include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, organic acids such as trifluoroacetic acid or Lewis acids such as B-bromocatecholborane (Lewis acids are more preferred and the B-bromocatecholborane is most preferred).
The base employable here is not particularly limited, provided that it does not affect other parts of the compounds, and preferred examples include metal alkoxides such as sodium methoxide, alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide and ammonias such as aqueous ammonia and conc. ammonia-methanol.
Incidentally, isomerization may occur in hydrolysis with a base.
The solvent employable here is not particularly limited, provided that it is usually used in hydrolysis reactions, and preferred examples include water; organic solvents such as alcohols, e.g. methanol, ethanol and n-propanol, and ethers, e.g. tetrahydrofuran and dioxane, and mixtures of these organic solvents and water.
While the reaction temperature and time vary depending on the starting material, the solvent, the acid or base used, etc. and are not particularly limited, the reaction is usually carried out at a temperature of from 0xc2x0 C. to 150xc2x0 C. for the period of from 1 to 10 hours to control any side reactions.
In the case where G2 is an aralkyl group or an aralkyloxycarbonyl group, the removal method of G2 is preferably achieved by bringing a compound into contact with a reducing agent in a solvent (preferably a catalytic reduction at a normal temperature in the presence of a catalyst) or by using an oxidizing agent.
The solvent employable in the removal by catalytic reduction is not particularly limited, provided that it does not affect the present reaction, and preferred examples include alcohols such as methanol, ethanol and isopropanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as toluene, benzene and xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, aliphatic acids such as acetic acid and mixtures of these organic solvents and water.
The catalyst employable here is not particularly limited, provided that is conventionally used in catalytic reduction reactions, and preferred examples include palladium on carbon, palladium hydroxide, Raney nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride and palladium-barium sulfate.
The pressure is not particularly limited and the reaction is usually carried out at a temperature of from 1 to 10 atms.
While the reaction temperature and time vary depending on the starting material, the solvent and the kind of catalyst employed, the reaction is usually carried out at a temperature of from 0 to 100xc2x0 C. for the period of from 5 minutes to 24 hours.
The solvent employable in the removal by oxidation is not particularly limited, provided that it does not affect the present reaction, and a hydrous organic solvent is preferred.
Preferred examples of such an organic solvent include ketones such as acetone, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, nitriles such as acetonitrile, ethers such as diethyl ether, tetrahydrofuran and dioxane, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoric triamide and sulfoxides such as dimethyl sulfoxide.
The oxidizing agent employable here is not particularly limited, provided that it is used in oxidation, and preferred examples include potassium persulfate, sodium persulfate, cerium ammonium nitrate (CAN) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).
While the reaction temperature and time vary depending on the starting material, the kind of solvent and the catalyst, the reaction is usually carried out at a temperature of from 0xc2x0 C. to 150xc2x0 C. for the period of from 10 minutes to 24 hours.
In the case where G2 is an alkenyloxycarbonyl group, the removal can usually be accomplished using conditions similar to those for the removal reaction in the case where the amino protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group.
In the case where G2 is an allyloxycarbonyl group, particularly, the removal can be carried out easily by using palladium and triphenylphosphine or nickel tetracarbonyl with less side reactions.
While the G1 group may be removed in the present step, the carboxyl group can be protected again according to the following methods:
 less than Method 1 greater than 
The method 1 is to react the resulting carboxylic acid derivative with a compound of formula G1-Lxe2x80x2 (wherein G1 has the same meaning as defined above and Lxe2x80x2 represents a leaving group) in a solvent (the solvent employable here is not particularly limited, provided that it does not inhibit the reaction and dissolves the starting material to some extent, and preferred examples include aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitrites such as acetonitrile and isobutyronitrile; and amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide) in the presence of a base [the base employable here is not particularly limited, provided that it is used as a base in conventional reactions, and preferred examples include inorganic bases such as alkali metal carbonates, e.g. sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydrogencarbonates, e.g. sodium hydrogencarbonate, potassium hydrogencarbonate and lithium hydrogencarbonate; alkali metal hydrides, e.g. lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide; alkali metal fluorides, e.g. sodium fluoride and potassium fluoride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide and lithium methoxide; alkali metal mercaptans such as sodium methylmercaptan and sodium ethylmercaptan; organic bases such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and organic metal bases such as butyllithium, lithium diisopropylamide and lithium bis(trimethylsilyl)amide) usually at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C. (preferably from 0 to 100xc2x0 C.) for a period of from 0.5 to 10 hours.
 less than Method 2 greater than 
The method 2 is to react the resulting carboxylic acid derivatives with a compound of formula G1xe2x80x94OH (wherein G1 has the same meaning as defined above) in a solvent in the presence or absence of a base with the following xe2x80x9ccondensation agentxe2x80x9d.
Examples of the condensation agent employable in the present reaction include:
(1) a combination of a phosphoric ester, such as diphenylphosphoryl azide or diethyl cyanophosphate, and a below-mentioned base;
(2) a carbodiimide, such as 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; a combination of the carbodiimides and a below-mentioned base; or a combination of the carbodiimide and an N-hydroxy compound, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbomene-2,3-dicarboxyimide;
(3) a combination of a disulfide, such as 2,2xe2x80x2-dipyridyl disulfide or 2,2xe2x80x2-dibenzothiazolyl disulfide, and a phosphine, such as triphenylphosphine or tributylphosphine;
(4) a carbonate, such as N,Nxe2x80x2-disuccinimidyl carbonate, di-2-pyridyl carbonate or S,Sxe2x80x2-bis(1-phenyl-1H-tetrazol-5-yl)dithiocarbonate;
(5) a phosphinic chloride, such as N,Nxe2x80x2-bis(2-oxo-3-oxazolidinyl)phosphinic chloride;
(6) an oxalate, such as N,Nxe2x80x2-disuccinimidyl oxalate, N,Nxe2x80x2-diphthalimide oxalate, N,Nxe2x80x2-bis(5-norbomene-2,3-dicarboxyimidyl)oxalate, 1,1xe2x80x2-bis(benzotriazolyl)-oxalate, 1,1xe2x80x2-bis(6-chlorobenzotriazolyl)oxalate or 1,1xe2x80x2-bis(6-trifluoromethylbenzotriazolyl)oxalate;
(7) a combination of the phosphine and an azodicarboxylic acid ester or an azodicarboxyamide, such as diethyl azodicarboxylate or 1,1xe2x80x2-(azodicarbonyl)-dipiperidine; a combination of the phosphines and a below-mentioned base;
(8) an N-lower alkyl-5-arylisoxazolium-3xe2x80x2-sulfonate, such as N-ethyl-5-phenylisoxazolium-3xe2x80x2-sulfonate;
(9) a diheteroaryldiselenide, such as di-2-pyridyldiselenide;
(10) an arylsulfonyltriazolide, such as p-nitrobenzenesulfonyltriazolide;
(11) a 2-halo-1-lower alkylpyridinium halaide, such as 2-chloro-1-methylpyridinium iodide;
(12) an imidazole, such as 1,1xe2x80x2-oxalyldiimidazole or N,Nxe2x80x2-carbonyl-diimidazole;
(13) a 3-lower alkyl-2-halogen-benzothiazolium fluoroborate, such as 3-ethyl-2-chloro-benzothiazolium fluoroborate;
(14) a 3-lower alkyl-benzothiazole-2-selone, such as 3-methylbenzothiazole-2-selone;
(15) a phosphate, such as phenyldichlorophosphate or polyphosphate;
(16) a halosulfonyl isocyanate, such as chlorosulfonyl isocyanate;
(17) a halosilane, such as trimethylsilyl chloride or triethylsilyl chloride;
(18) a combination of a lower alkanesulfonyl halide, such as methanesulfonyl chloride, and a below-mentioned base;
(19) an N,N,Nxe2x80x2,Nxe2x80x2-tetra-lower alkyl haloformamidium chloride, such as N,N,Nxe2x80x2,Nxe2x80x2-tetramethylchloroformamidium chloride.
Of these, the carbodiimides or a combination of a phosphine and an azodicarboxylic ester or azodicarboxyamide is preferred.
The solvent employable here is not particularly limited, provided that it does not inhibit the reaction and dissolves the starting material to some extent, and preferred examples include aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; and amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide.
The base employable here is not particularly limited, provided that it is used as a base in conventional reactions, and preferred examples include organic bases such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline and N,N-diethylaniline.
Incidentally, 4-(N,N-dimethylamino)pyridine and 4-pyrrolidinopyridine can be used in a catalytic amount by combining it with other bases, and further a dehydrating agent such as molecular sieves, quatemary ammonium salts such as benzyltriethylammonium chloride and tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6 and an acid scavenger such as 3,4-dihydro-2H-pyrid[1,2-a]pyrimidine-2-one can be also added thereto in order to effectively carry out the reaction.
The reaction is usually carried out at a temperature of from xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably from 0xc2x0 C. to 50xc2x0 C.
The reaction time varies mainly depending on the reaction temperature, the starting material, the reagent and the kind of the solvent used, and is usually for a period of from 10 minutes to 3 days, preferably from 30 minutes to 1 day.
 less than Method 3 greater than 
In the case where the protecting group is a lower alkyl group, Method 3 is a method to react the resulting carboxylic acid derivatives with a corresponding alcohol, such as methanol, ethanol, propanol or butanol, in a solvent (the solvent employable here is not particularly limited, provided that it does not inhibit the reaction and dissolves the starting material to some extent, and preferred examples include alcohols identical to the reagent; aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitriles such as acetonitrile and isobutyronitrile; and amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide, of which the alcohols identical to the reagent are preferred) in the presence of an acid catalyst (the acid catalyst employable here is not particularly limited, provided that it is used as an acid catalyst in conventional reactions, and preferred examples include Bronsted acids such as inorganic acids, e.g. hydrogen chloride, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid, and organic acids, e.g. acetic acid, formic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid, and Lewis acids, e.g. boron trichloride, boron trifluoride and boron tribromide, and acidic ion-exchange resins) at a temperature of from 0xc2x0 C. to 150xc2x0 C. (preferably from 50xc2x0 C. to 100xc2x0 C.) for a period of from 10 minutes to 24 hours (preferably from 30 minutes to 10 hours). 
In the formulae,
R4, R5, R7, R8, A, G1, G2 and Q have the same meanings as defined above; and
G3 represents an amide protecting group.
The xe2x80x9camide protecting groupxe2x80x9d in the definition of G3 means a protecting group which may be removed by a chemical process such as hydrogenolysis, hydrolysis, electrolysis and photolysis, and preferred examples include lower alkoxy lower alkyl groups such as the above-mentioned xe2x80x9clower alkoxymethyl groupsxe2x80x9d; aralkyloxymethyl groups such as benzyloxymethyl; and 2-[tri(lower alkyl)silyl]ethoxy lower alkyl groups such as 2-(trimethylsilyl)ethoxymethyl, of which methoxymethyl, benzyloxymethyl and 2-(trimethylsilyl)ethoxymethyl groups.
Steps 9, 10, 11 and 13 in Method C are carried out in a similar manner to the procedures described in Steps 4, 8, 1 and 3 respectively.
Step 12 is a process to prepare the compound of formula (1e) of the present invention by removing the two protecting groups (the G1 and G2 groups) of the compound of formula (12), and is carried out in a similar manner to the procedure described in Steps 2 or 8. In the present invention, while the compound of formula (13) or (14), which is a compound of formula (12) in which one of the protecting groups is removed, may be produced, it can be converted into a compound of formula (Ie) by further carrying out a deprotection reaction in a similar manner to the procedure described above (Steps 12a and 12b). 
In the above formulae,
R3a, R4, R5, R7, R8, A, G1, G3 and L have the same meanings as defined above.
Steps 14 and 16 in Method D are carried out in a similar manner to the procedures described in Steps 4 and 3 in Method A respectively and Step 15 (15a and 15b) is carried out in a similar manner to the procedures described in Step 12 (12a and 12b). 
In the formulae,
R3a, R4, R5, R6, G1, L and Q have the same meanings as defined above; and
p is an integer of from 1 to 6, preferably from 2 to 4.
Steps 17, 18, 21a, 21b, 22 and 23 in Method E are carried out in a similar manner to the procedures described in Steps 1, 4, 4-a), 4-b), 2 and 3 respectively.
Step 19 is a process to prepare an ester derivative of formula (22) by hydrolizing the lactone compound of formula (20) followed by reacting the resulting compound with a halide compound of formula (21).
1) While the former hydrolysis reaction can be accomplished by a method generally used in organic synthetic chemistry, the method of treating the lactone compound of formula (20) with a base in a solvent is preferred.
The base employable here is not limited, provided that it does not affect other parts of the compound, and preferred examples include metal alkoxides such as sodium methoxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide and ammonia such as aqueous ammonia and conc. ammonia-methanol.
The solvent employable here is not limited provided that it is usually used in hydrolysis reactions, and preferred examples include water; organic solvents such as alcohols, e.g. methanol, ethanol and n-propanol, and ethers, e.g. tetrahydrofuran and dioxane, and mixtures of these organic solvents and water.
While the reaction temperature and time vary depending on the starting material, the solvent, the base used, etc. and are not particularly limited, the reaction is usually carried out at a temperature of from 0xc2x0 C. to 150xc2x0 C. for a period of from 1 to 10 hours to control any side reactions.
2) The latter protection reaction of the carboxyl group can be carried out in a similar manner to that described in Step 8. It is preferably carried out according to Method 1 described in Step 8.
Step 20 is a process to prepare the compound of formula (23) by converting the hydroxyl group of the compound of formula (22) into a halogen atom and, for example, a fluorination reaction with diethylamino sulfide trifluoride (DAST); a chlorination reaction with thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or triphenylphosphine/carbon tetrachloride; a bromination reaction with hydrobromic acid, thionyl bromide, phosphorus tribromide or triphenylphosphine/carbon tetrabromide; or an iodination reaction with hydroiodic acid or phosphorus triiodide is carried out according to the method described in xe2x80x9cW. J. Middleton [J. Org. Chem., 40, p. 574 (1975)].xe2x80x9d
In the formulae,
R3a, R4, R5, R6, L and Q have the same meanings as defined above; and
G4 represents a hydroxyl protecting group.
The xe2x80x9chydroxyl protecting groupxe2x80x9d in the definition of G4 means a protecting group which may be removed by a chemical process such as hydrogenolysis, hydrolysis, electrolysis and photolysis, and preferred example include the above-mentioned xe2x80x9csilyl groupsxe2x80x9d, of which the above-mentioned xe2x80x9ctri-lower alkylsilyl groupsxe2x80x9d are more preferred, and a trimethylsilyl, triethylsilyl, isopropyldimethylsilyl and t-butyldimethylsilyl groups are particularly preferred.
Step 24 is a process to prepare a compound of formula (26) by reacting the amino group of serinol (25) with the sulfonyl halide compound of formula (2) and is carried out in a similar manner to the procedure described in Step 1.
Step 25 is a process to prepare a compound of formula (27) by modifying the N atom in the sulfonamide moiety of the compound of formula (26) and is carried out in a similar manner to the procedure described in Step 4.
Step 26 is a process to prepare a compound of formula (29) by protecting one of two hydroxyl groups of the diol compound of formula (27) and is carried out, for example, by reacting it with a tri-lower alkylsilyl halide compound of formula (28). The reaction is carried out, for example, according to the process for the synthesis of silyl ethers described in xe2x80x9cProtective Groups in Organic Synthesis, John Wiley and Sons, New York 1991.xe2x80x9d
Step 27 is a process to prepare a compound of formula (30) by reacting the compound of formula (29) with the compound of formula (7) and is carried out in a similar manner to the procedure described in Step 4-a).
Step 28 is a process to prepare a compound of formula (31) by removing the hydroxyl protecting group from the compound (30) and is carried out, for example, according to the decomposition process of silyl ethers described in xe2x80x9cProtective Groups in Organic Synthesis, John Wiley and Sons, New York 1991.xe2x80x9d
Step 29 is a process to prepare an aldehyde compound of formula (32) by oxidizing the hydroxyl group of the compound of formula (31) and is carried out, for example, by using chromic acid, manganese dioxide, dimethyl sulfoxide, etc. according to the processes described in xe2x80x9cK. Omura, A. K. Sharma and D. Swem [J. Org. Chem., 41, p. 957 (1976)] and S. L. Huang, K. Omura and D. Swem [Tetrahedron, 34, p. 1651 (1978)].xe2x80x9d
Step 30 is a process to prepare a compound of formula (Ik) of the present invention by oxidizing the aldehyde compound of formula (32) and is carried out by using permanganic acids, chromic acid, peroxides, oxygen, halogen, hypohalous acids, halous acids, halogen acids, nitric acid, etc. according to the processes described in xe2x80x9cT. Kageyama, Y Ueno and M. Okawara [Synthesis, p. 815 (1983)] and C. D. Hurd, J. W. Garrett and E. N. Osborne [J. Am. Chem. Soc., 55, p. 1082 (1933)].xe2x80x9d
Step 31 is a process to prepare a compound of formula (Il) of the present invention by hydroxyamidation of the compound of formula (Ik) of the present invention and is carried out in a similar manner to the procedure described in Step 3.
The starting materials, namely the compounds (1), (6), (18) and (25), and side-starting materials, namely the compounds (2), (4), (7), (9), (21) and (28), are known per se or can be obtained from known compounds by treatment according to known methods.
After completion of each reaction described above, the desired compound is isolated from the reaction mixture in a conventional manner.
For example, it is obtained by neutralizing the reaction mixture as needed, removing the insoluble matters by filtration, if any, adding organic solvents which are not miscible each other, such as water and ethyl acetate, washing with water or the like, separating the organic layer containing the desired compound, drying it over anhydrous magnesium sulfate or the like and then distilling off the solvent.
If necessary, the desired compound thus obtained can be isolated and purified by using a conventional method such as recrystallization or reprecipitation and chromatography in which a method ordinarily employed for the isolation and purification of an organic compound in combination as needed and eluting using a proper eluant. Examples of chromatography include adsorption column chromatography using a carrier such as silica gel, alumina or magnesium-silica gel type Florisil, chromatography using a synthetic adsorbent, for example, partition column chromatography using a carrier such as Sephadex LH-20 (product of Pharmacia), Amberlite XAD-11 (product of Rohm and Haas) or Diaion HP-20 (product of Mitsubishi Chemical), ion exchange chromatography or normal-phase-reverse-phase column chromatography (high-performance liquid chromatography) using a silica gel or alkylated silica gel.
Since the compounds of formula (I) of the present invention or pharmacologically acceptable salts, esters or other derivatives thereof exhibit excellent excellent MMP-13 inhibiting activity and an aglycanase inhibiting activity, it is effective as a medicament (particularly, an agent for the prevention or treatment of arthritis, such as osteoarthritis and chronic rheumatism, or a medicament for inhibiting metastasis, invasion or growth of cancer), and examples of the administration route include oral administration in the form of tablets, capsules, granules, powders or syrups and parenteral administration in the form of injections or suppositories. Such formulations can be prepared in a known manner by using carriers such as an excipient, lubricant, binder, disintegrator, stabilizer, corrigent or diluent.
Examples of the excipient include organic excipients, e.g., sugar derivatives such as lactose, sucrose, dextrose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, xcex1-starch, dextrin and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose and sodium intemally-crosslinked carboxymethylcellulose; gum arabic; dextran; and pullulan; and inorganic excipients, e.g., silicate derivatives such as soft silicic acid anhydride, synthetic aluminum silicate and magnesium aluminometasilicate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate.
Examples of the lubricant include stearic acid; metal salts of stearic acid such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as bee gum and spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium salts of an aliphatic acid; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acid derivatives such as silicic acid anhydride and silicic acid hydrate; and starch derivatives exemplified above as the excipient.
Examples of the binders include polyvinylpyrrolidone, Macrogol and compounds similar to those exemplified above as the excipient.
Examples of the disintegrator include compounds similar to those exemplified above as the excipient and chemically modified starch or cellulose derivatives such as sodium cross carmellose, sodium carboxymethyl starch and crosslinked polyvinylpyrrolidone.
Examples of the stabilizer include paraoxybenzoate esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenol derivatives such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.
Examples of the corrigent include ordinarily-employed sweeteners, acidifiers and flavors.
The dose of the compound (I) or a pharmacologically acceptable salt, ester or derivative thereof according to the present invention will vary depending on the condition, age of the patient, or administration route. Orally, it is administered to an adult in an amount of 0.1 mg (preferably 1 mg) a day as a lower limit and 1000 mg (preferably 100 mg) a day as an upper limit. It is desired to be administered in one to several portions depending on the condition of the patient. Intravenously, it is administered to an adult in an amount of 0.01 mg (preferably 0.1 mg) a day as a lower limit and 100 mg (preferably 10 mg) a day as an upper limit. It is desired to be administered in one to several portions per day depending on the condition of the patient.